Reactions of the cumyloxyl and benzyloxyl radicals with strong hydrogen bond acceptors. Large enhancements in hydrogen abstraction reactivity determined by substrate/radical hydrogen bonding

Article abstract of DOI:10.1021/jo3019889

A kinetic study on hydrogen abstraction from strong hydrogen bond acceptors such as DMSO, HMPA, and tributylphosphine oxide (TBPO) by the cumyloxyl (CumO^?) and benzyloxyl (BnO^?) radicals was carried out in acetonitrile. The reactions

Full text of DOI:10.1021/jo3019889

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pubs.acs.org/joc
Reactions of the Cumyloxyl and Benzyloxyl Radicals with Strong
Hydrogen Bond Acceptors. Large Enhancements in Hydrogen
Abstraction Reactivity Determined by Substrate/Radical Hydrogen
Bonding
Michela Salamone, Gino A. DiLabio,* and Massimo Bietti*,†
†
,‡,§
†
Dipartimento di Scienze e Tecnologie Chimiche, Universita
̀
“Tor Vergata”, Via della Ricerca Scientifica, 1 I-00133 Rome, Italy
‡
National Institute for Nanotechnology, National Research Council of Canada, 11421 Saskatchewan Drive, Edmonton, Alberta T6G
2
M9, Canada
§
Department of Physics, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
*
S Supporting Information
ABSTRACT: A kinetic study on hydrogen abstraction from
strong hydrogen bond acceptors such as DMSO, HMPA, and
•
tributylphosphine oxide (TBPO) by the cumyloxyl (CumO )
•
and benzyloxyl (BnO ) radicals was carried out in acetonitrile.
•
The reactions with CumO were described in terms of a direct
hydrogen abstraction mechanism, in line with the kinetic
deuterium isotope effects, k /k , of 2.0 and 3.1 measured for
H
D
reaction of this radical with DMSO/DMSO-d and HMPA/
6
HMPA-d . Very large increases in reactivity were observed on
18
•
•
•
•
3
4
going from CumO to BnO , as evidenced by k (BnO )/k (CumO ) ratios of 86, 4.8 × 10 , and 1.6 × 10 for the reactions with
H
H
•
HMPA, TBPO, and DMSO, respectively. The k /k of 0.91 and 1.0 measured for the reactions of BnO with DMSO/DMSO-d
H
D
6
•
•
and HMPA/HMPA-d , together with the k (BnO )/k (CumO ) ratios, were explained on the basis of the formation of a
1
8
H
H
hydrogen-bonded prereaction complex between the benzyloxyl α-C−H and the oxygen atom of the substrates followed by
hydrogen abstraction. This is supported by theoretical calculations that show the formation of relatively strong prereaction
complexes. These observations confirm that in alkoxyl radical reactions specific hydrogen bond interactions can dramatically
influence the hydrogen abstraction reactivity, pointing toward the important role played by structural and electronic effects.
INTRODUCTION
One aspect of these processes that is attracting considerable
interest is the possible role of specific substrate−radical
interactions. A number of recent computational studies on
the hydrogen abstraction reactions from amino acids and model
■
Hydrogen atom abstraction is one of the most fundamental
chemical reactions and plays a major role in a variety of
important chemical and biological processes. These reactions
•
peptides by HO have indicated that in these processes the
1
,2
are involved in processes such as lipid peroxidation, the
formation of substrate−radical prereaction complexes can play
3
1,4
antioxidant activity of vitamin E, and other natural and
43−46
an important role;
this may account for the regioselectivity
5
synthetic phenolic and nonphenolic antioxidants, the reactions
observed in these reactions, where abstraction occurs
6
−9
of various substrates with cytochrome P450
and other
the degradation of volatile organic
preferentially from the stronger side-chain C−H bonds as
1
0,11
metalloenzymes,
47−49
compared to the weaker backbone C−H bonds.
12
compounds in the atmosphere, a3s−w17ell as in a large number
Experimental evidence for the formation of hydrogen bonded
prereaction complexes has been also provided in three recent
studies on the hydrogen abstraction reactions from C−H and
1
of synthetically useful procedures.
The abstracting species can be a radical or a different species
such as a transition metal complex and an increasing number of
studies have been devoted to the mechanistic understanding of
the hydrogen abstraction reactions by these species.
Among the abstracting radicals, highly reactive oxygen centered
5
0−52
O−H bonds by transition metal complexes.
In this context, we recently carried out a time-resolved
kinetic study on the hydrogen abstraction reactions from
1
8−27
•
•
alkylamines by the cumyloxyl (PhC(CH ) O , CumO ) and
3
2
•
•
•
•
53−55
radicals such as hydroxyl (HO ) and alkoxyl (RO ) have
received most attention, as these radicals are able to abstract an
hydrogen atom from a large variety of substrates, and
accordingly their hydrogen abstraction reactivity has been
benzyloxyl (PhCH O , BnO ) radicals.
These studies
2
revealed large differences in reactivity between the two radicals.
Received: September 12, 2012
Published: November 15, 2012
2
8−42
studied in detail.
©
2012 American Chemical Society
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With all substrates, an increase in reactivity was observed on
substrates, specifically those commonly used as solvents. The
substrate HBA ability can be quantitatively expressed in terms
of Abraham’s β2H parameter, which ranges in magnitude from
0.00 for a non-HBA substrate such as an alkane to 1.00 for
•
•
going from CumO to BnO , as shown by the hydrogen
•
•
abstraction rate constant ratios, k (BnO )/k (CumO ), that
H
H
varied between 2.8 for the reactions with the relatively hindered
triisobutylamine to >1000 for the reactions with amines such as
59
hexamethylphosphoric acid triamide (HMPA). Alkylamines
are relatively good hydrogen bond acceptors, being charac-
terized by β2H values between 0.58 and 0.73 (β2H = 0.58−0.62
for tertiary amines (0.67 for triethylamine) and 0.69−0.73 for
1,4-diazabicyclo[2,2,2]octane (DABCO), 1-azabicyclo[2,2,2]-
octane (ABCO), and tert-octylamine. Opposite reactivity trends
were observed for the two radicals along different alkylamine
series: kH values were found to decrease on going from the
59
primary and secondary amines).
•
tertiary to the primary amine for the reactions with CumO ,
Along this line, we have carried out a detailed time-resolved
•
whereas an increase in reactivity was observed in the
kinetic study in acetonitrile solution on the reactions of CumO
•
•
corresponding reactions with BnO . These results were
and BnO , selecting as hydrogen atom donors dimethyl
explained on the basis of different reactive pathways for the
two radicals. The reactions of CumO were described in all
sulfoxide (DMSO), tributylphosphine oxide (TBPO), and
•
H
HMPA, all characterized by very high HBA abilities (β
=
2
59
cases in terms of a direct hydrogen abstraction mechanism, i.e.,
a reaction that proceeds through the interaction of the radical
center with the amine α-C−H and/or N−H bond, in line with
0.78, 0.98, and 1.00, respectively), whose structures are
displayed in Chart 1. For mechanistic purposes, the reactions of
dimethyl sulfoxide-d (DMSO-d ) and hexamethylphosphoric
6
6
3
5,39,40,56
previous studies,
as described in Scheme 1 for a
acid triamide-d18 (HMPA-d ) have also been investigated.
18
representative tertiary amine.
Chart 1
Scheme 1
•
With BnO , the kinetic data were explained on the basis of a
mechanism that proceeds through the rate-determining
formation of a hydrogen bonded complex between the
•
57
relatively acidic α-C−H of BnO and the amine lone pair,
wherein fast hydrogen abstraction occurs (Scheme 2, paths a
5
3−55
and b).
This mechanistic picture is well supported by the
53,55
results of computational studies.
Limited information is available on the reactivity of these
substrates in hydrogen abstraction reactions, and to the best of
our knowledge, no information is presently available on their
reactions with alkoxyl radicals. DMSO and HMPA are very
important compounds that are widely used as solvents for a
variety of reactions. In addition, DMSO is a compound of
atmospheric interest, that has been identified as an important
intermediate in the atmospheric oxidation of dimethyl sulfide
Scheme 2
60
(
DMS), while HMPA, due to its toxicity, represents an
61
environmental contaminant of potential concern. Moreover,
HMPA is routinely employed as a cosolvent in reductive radical
62
chemistry based on the use of samarium(II) reagents.
Therefore, the assessment of the reactivity of these substrates
in hydrogen abstraction reactions appears of great importance.
RESULTS
With the relatively hindered triisobutylamine, steric effects
prevent the formation of a sufficiently stable complex, and the
■
•
•
The reactions of CumO and BnO , with the substrates shown
in Chart 1, were studied by laser flash photolysis (LFP). The
alkoxyl radicals were generated by 266 nm LFP of nitrogen-
saturated acetonitrile solutions (T = 25 °C) containing dicumyl
or dibenzyl peroxide, as described in eq 1.
•
reaction of this substrate with BnO has been described as a
55
direct hydrogen abstraction (Scheme 2, path c).
On the basis of this reaction scheme, it clearly appears that in
the reactions of alkoxyl radicals with alkylamines specific
substrate−radical hydrogen-bond interactions can dramatically
influence the hydrogen abstraction reactivity, where a major
role is played by substrate sterics and hydrogen bond acceptor
(
HBA) ability, and by the possibility for the radical to act as a
hydrogen-bond donor (HBD).
In view of the relevance of these reactions and to develop a
clearer mechanistic understanding of the role of substrate−
radical hydrogen-bond interactions on hydrogen abstraction
reactions by alkoxyl radicals, we thought it important to study
•
•
In acetonitrile solution, CumO and BnO are characterized
by an absorption band in the visible region of the spectrum
centered at 485 and 460 nm, respectively.
•
•
63,64
the reactions of CumO and BnO with very strong HBA
Under these
1
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The Journal of Organic Chemistry
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•
64,65
conditions, CumO decays mainly by C−CH β-scission,
Table 1. Second-Order Rate Constants (k ) for the
H
3
•
•
while the decay of BnO can be mainly attributed to hydrogen
abstraction from the solvent.
The kinetic studies were carried out by LFP following the
decay of the CumO and BnO visible absorption bands at 490
and 460 nm, respectively, as a function of the substrate
concentration. The observed rate constants (kobs) gave
excellent linear relationships when plotted against substrate
concentration and the second-order rate constants for hydro-
Reactions of the Cumyloxyl (CumO ) and Benzyloxyl
58
•
(BnO ) Radicals with Different Substrates
a
(M−1 s−1
•
•
k
H
)
•
k (BnO )/
H
H
CumO•
BnO•
k (CumO )
•
substrate
DMSO
1.8 ± 0.1 × 104
9.0 ± 0.2 × 103
2.0
2.88 ± 0.04 × 108
3.16 ± 0.04 × 108
0.91
1.6 × 10
3.5 × 10
4
4
DMSO-d6
k /k
D
gen abstraction from the substrates (k ) by the alkoxyl radicals
were obtained from the slopes of these plots. Figure 1 shows
H
H
7
9
HMPA
HMPA-d18
k /k
1.87 ± 0.02 × 10
6.03 ± 0.03 × 106
1.6 ± 0.1 × 10
1.58 ± 0.02 × 109
86
262
3.1
1.0
H
D
5
9
3
TBPO
5.6 ± 0.4 × 10
2.68 ± 0.03 × 10
4.8 × 10
a
Measured in N -saturated MeCN solution at T = 25 °C employing
2
2
66 nm LFP: [dicumyl peroxide] = 10 mM or [dibenzyl peroxide] = 8
mM. kH values were determined from the slope of the kobs vs
substrate] plots, where in turn k values were measured following
[
obs
•
•
the decay of the CumO or BnO visible absorption bands at 490 and
4
60 nm, respectively. Average of at least two determinations.
Scheme 3
The very low kH value measured for this reaction can be
explained on the basis of polar effects, as hydrogen abstraction
reactions from electron-deficient C−H bonds by electrophilic
Figure 1. Plots of the observed rate constant (kob •s ) against [HMPA]
for the reactions of the cumyloxyl radical (CumO , filled circles) and
benzyloxyl radical (BnO , empty circles), measured in nitrogen-
2
4,66,67
•
alkoxyl radicals are known to be relatively slow processes.
The indication of DMSO as a very poor hydrogen atom donor
has been also obtained from a study of the benzophenone-
saturated MeCN solution at T = 25 °C by following the decay of
•
•
CumO and BnO at 490 and 460 nm, respectively. From the linear
68
•
5 −1
regression analysis: CumO + HMPA: intercept = 7.44 × 10 s , k =
photosensitized alkylation of arylalkenes.
H
7
−1 −1
2
•
1
1
.87 × 10 M s , r = 0.9998; BnO + HMPA: intercept = 6.55 ×
Lissi and co-workers performed a product study of the
5
−1
9
−1 −1
2
0 s , k = 1.73 × 10 M s , r = 0.9999.
reaction of dimethyl sulfide (DMS) with the tert-butoxyl radical
H
•
(
t-BuO ) in benzene solution, and showed that the reaction
6
proceeds through hydrogen abstraction with k = 3.5 × 10
H
−1
−1
69
•
•
the plots of k vs [HMPA] for the reactions of this substrate
obs
M
s
at T = 37 °C. t-BuO and CumO are known to
40,70
with CumO (filled circles) and BnO• (open circles) for
measurements carried out in acetonitrile solution at T = 25 °C.
Additional plots for the hydrogen abstraction reactions by
•
display very similar hydrogen abstraction reactivities,
and
accordingly, the kH value measured for the reaction of the
former radical with DMS can be conveniently compared with
•
•
•
CumO and BnO from the other substrates are displayed in
the Supporting Information (Figures S1−S8). All of the kinetic
data thus obtained are collected in Table 1 together with the
the value measured for the reaction of CumO with DMSO (k
H
4
−1 −1
= 1.8 × 10 M s , at T = 25 °C). The comparison shows that
a greater than 2 order of magnitude increase in k is observed
H
•
•
pertinent k (BnO )/k (CumO ) and k /k ratios.
on going from DMSO to DMS, despite the very similar
recommended bond dissociation energies (BDEs) available for
the C−H bonds of these substrates (BDE = 94, and 93.7 kcal
H
H
H
D
DISCUSSION
■
•
−1
71,72
Starting from the reactions of CumO , a striking observation
derived from the analysis of the data displayed in Table 1 is the
extremely low rate constant measured for the reaction of this
radical with DMSO, k = 1.8 × 10 M s , a value that is
among the lowest known rate constants for bimolecular
mol for DMSO and DMS, respectively),
where, however,
the available BDE value for DMSO has been estimated on the
72
basis of a thermochemical cycle. In an effort to explore this
apparent discrepancy, we calculated the BDEs for the C−H
bonds of DMSO and DMS, as well as of HMPA, using a
previously outlined procedure based on the density-functional
4
−1 −1
H
•
reactions of CumO . The observation of a sizable kinetic
73
deuterium isotope effect (k /k = 2.0) in the reactions of
theory (DFT) B3P86/6-311G(2d,2p) method. The calcu-
H
D
•
CumO with DMSO and DMSO-d strongly supports the
lated C−H BDEs for these substrates are displayed in Table 2,
6
7
1,72
hypothesis that this reaction can be described as a direct
along with the available experimental values.
To the best of
hydrogen abstraction from the methyl group of DMSO (and
our knowledge, no BDE value is presently available for the C−
H bonds of HMPA.
DMSO-d ) to give a methylsulfinyl methyl radical as described
6
in Scheme 3.
The data displayed in Table 2 show very similar calculated
and experimental BDE values for DMS. However, calculations
predict the C−H BDE for DMSO to be 8.1 kcal/mol higher
than the recommended literature value. Following computation
validation studies (see the Supporting Information), we
The value displayed in Table 1 represents the first absolute
rate constant for hydrogen abstraction from DMSO by an
alkoxyl radical and provides a quantitative evaluation of the
hydrogen atom donor ability of DMSO in these reactions.
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Table 2. Calculated and Experimental C−H Bond
alkoxyl radicals with trivalent organophosphorus compounds
Dissociation Energies (BDEs) for DMSO, DMS, and HMPA
(L P) proceed by addition of the radical to the phosphorus
3
−1
•
78,80
(
kcal mol )
center to give intermediate phosphoranyl radicals L P OR.
3
On the other hand, the addition of free radicals to pentavalent
BDE
organophosphorus compounds of the type L PO has been
3
a
molecule
calcd
exptl
discarded on thermochemical grounds, on the basis of the great
b
80
DMSO
DMS
102.1
95.2
94.4
94
strength of the PO bond. Along this line, the kH value
c
•
93.7
measured for the reaction of CumO with TBPO can be
HMPA
reasonably assigned to an hydrogen abstraction from the α-CH2
groups.
The data displayed in Table 1 show that with all three
a
b
B3P86/6-311G(2d,2p) as described in ref 73. Experimental data
c
taken from ref 72. Experimental data taken from ref 71.
substrates very large increases in k have been observed on
H
•
•
4
7
going from CumO to BnO : k = 1.8 × 10 , 1.87 × 10 , and
conclude that our computational BDE value for the C−H
bonds of DMSO is likely to be closer to the true value than the
presently available literature value. On the basis of these
H
5
−1 −1
•
5
.6 × 10 M s , for the reactions of CumO with DMSO,
8
HMPA, and TBPO, respectively, as compared to 2.88 × 10 ,
9
9
−1 −1
1
.6 × 10 , and 2.68 × 10 M
s
for the corresponding
findings, it appears that the large decrease in k observed for
H
•
•
reactions with BnO . The increase in reactivity can be
quantitatively expressed by the rate constant ratios
the reactions of CumO on going from DMS to DMSO can be
mostly associated to the BDE differences in the C−H bonds of
•
•
3
k (BnO )/k (CumO ) = 86 and 4.8 × 10 for HMPA and
these substrates.
H
H
4
Table 1 shows that a rate constant k = 1.87 × 10 M s−1
7
−1
TBPO, respectively, and as high as 1.6 × 10 for DMSO (3.5 ×
H
4
•
1
0 for DMSO-d ), where the magnitude of the ratio is strongly
has been measured for the reaction of CumO with HMPA.
6
influenced by the k values measured for the reactions with
CumO , i.e., by the reactivity displayed by these substrates in a
direct hydrogen abstraction reaction.
Also in this case, the observation of a kinetic deuterium isotope
H
•
•
effect, k /k = 3.1, in the reactions of CumO with HMPA and
H
D
HMPA-d , indicates that the reaction proceeds through
1
8
As mentioned above, large increases in reactivity were
previously observed for the hydrogen abstraction reactions
hydrogen abstraction from the methyl groups. To the best of
our knowledge, this represents the first absolute rate constant
for hydrogen abstraction from HMPA. The measured value is
in line with the computed C−H BDE given in Table 2, viz.,
•
•
from alkylamines on going from CumO to BnO , where with
the exclusion of the relatively hindered triisobutylamine, the kH
•
−1
values for reaction with BnO were at least 1 order of
9
4.4 kcal mol . The results indicate that HMPA is a fairly good
magnitude higher than those measured for the corresponding
hydrogen atom donor, displaying, in acetonitrile solution and
•
•
reactions of CumO , approaching the diffusion limit with the
on a per hydrogen basis, a reactivity toward CumO
substrates characterized by the most unhindered nitrogen
comparable to that observed for hydrogen abstraction from
6
−1 −1 74
9
the α-C−H bonds of THF (k = 5.8 × 10 M s ) and
atoms such as ABCO and DABCO (k
H
= 7.5 × 10 , and 1.05 ×
H
10
−1 −1
53−55
significantly higher than that observed for hydrogen abstraction
10
M
s , respectively).
The very high rate constants
6
−1 −1
74
•
from alkanes (k = 1.1 × 10 M
s
for cyclohexane).
measured for the reactions of BnO with the amines (k ≥ 3.0
H
H
9
−1 −1
•
•
HMPA is generally assumed to be an inert solvent in free-
radical reactions as evidenced by its wide use as a cosolvent in a
× 10 M s ), as well as the large k (BnO )/k (CumO )
H H
ratios (between 13 and 3380, for tripropylamine and tert-
octylamine, respectively), were rationalized in terms of the rate-
determining formation of a hydrogen bonded prereaction
62
variety of reactions involving samarium(II) compounds. The
present finding of a relatively high rate constant for hydrogen
•
•
abstraction from HMPA by CumO indicates that care should
complex between BnO and the amine, wherein hydrogen
be taken when this compound is employed in processes that
may produce reactive hydrogen-abstracting species.
abstraction occurs, as described in Scheme 2, paths a and b.
•
58
This behavior reflects the strong HBD ability of BnO , as well
59
It is interesting to note that evidence for hydrogen
abstraction from HMPA has been also provided in a study
on the photoreduction of aromatic ketones in HMPA solution,
where the formation of a cross-coupling product between the
ketyl radical of the ketone and the HMPA carbon-centered
radical formed following hydrogen abstraction from HMPA was
as the relatively high HBA ability of the alkylamines.
DMSO, TBPO, and HMPA are all characterized by
significantly higher HBA abilities than alkylamines, as measured
H
by the values of Abraham’s β
parameter of 0.78, 0.98, and
2
H
1.00, respectively, as compared to β
amines (0.67 for triethylamine) and 0.69−0.73 for primary and
secondary amines. We therefore expect that, in analogy to the
= 0.58−0.62 for tertiary
2
7
5
59
observed. This observation is in agreement with the
comparable hydrogen abstraction reactivity displayed by alkoxy
radicals and n,π* excited carbonyl compounds in their reactions
•
reaction of BnO with the amines, the reactions of DMSO,
•
TBPO, and HMPA with BnO occur by the rate-determining
76
•
with a variety of substrates. Very recently, the formation of
the HMPA radical following hydrogen abstraction from HMPA
formation of a hydrogen bonded complex between BnO and
the substrate, followed by a fast intramolecular hydrogen
abstraction step, as shown in Scheme 4 for DMSO.
57
•
81
by the hydrogen atom (H ) was proposed to occur in the
7
7
reduction of p-nitrophenol in HMPA solution by alkali metal.
Strong support for this mechanistic picture is provided by the
•
The data displayed in Table 1 show that CumO reacts with
TBPO with a rate constant k = 5.6 × 10 M s . This value
is at least 2 orders of magnitude lower than the values measured
study of the kinetic deuterium isotope effects for the reactions
5
−1 −1
•
of BnO with DMSO/DMSO-d and HMPA/HMPA-d . The
H
6
18
observation of k /k ratios of 0.91 and 1.0 clearly indicates that
H D
•
for the reactions of CumO with trialkyl and triarylphosphites
in these substrate/radical couples C−H bond cleavage does not
occur in the rate-determining step of the reaction. The
observation of an inverse kinetic deuterium isotope effect in
8
7
−1 −1
(
(RO) P: k = 6.2 × 10 and 5.5 × 10 M s , for R = Me and
3
8
−1 −1 78
t-Bu, respectively. (PhO) P: k = 2.5 × 10 M s ), and with
3
9
−1 −1 79
•
triphenylphosphine (Ph P: k = 1.04 × 10 M s ), in
the reaction of BnO with DMSO/DMSO-d6 may be a
3
acetonitrile solution. It is well-known that the reactions of
consequence of the slightly larger electron releasing effect
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−
1
Scheme 4
binding enthalpy of 6.4 kcal mol . However, this complex does
not orient the reactants in a manner that is favorable for
subsequent hydrogen abstraction along the lowest energy
pathway. This suggests that the complex may act as a kinetic
trap for the reactants, thus contributing to a lower rate constant
for the hydrogen abstraction reaction (see the Supporting
Information, Figure S10).
•
The prereaction BnO −DMSO complex can get to the TS
structure for C−H abstraction by a ca. 1.8 Å relative lateral
displacement of the DMSO and a rotation of ca. 45° of the
•
H CO group relative to the plane of the BnO ring (see Figure
2
2
b). The transition structure is about 10° off linearity with an
−1
enthalpy barrier of 3.7 kcal mol relative to the separated
reactants. Secondary interactions between the BnO aromatic
•
displayed by CD groups as compared to CH3 in some
3
8
3
ring and DMSO are also present.
The corresponding prereaction complex and TS structures
for the reactions of HMPA with BnO and CumO are shown
in the Supporting Information as Figures S11 and S12. As
compared to DMSO, the most stable prereaction complex
processes, an effect that would results in the formation of a
more stable prereaction complex and in a corresponding
increase in the rate of complex formation. However, this is at
most a working hypothesis that would require support from
additional studies.
•
•
•
structure between HMPA and BnO involves a stronger
Further support for this mechanistic picture comes from the
modeling of the prereaction complex and transition-state (TS)
−1
hydrogen-bond interaction (binding enthalpy of 8.4 kcal mol )
•
•
between the BnO α-C−H and the oxygen lone pair of HMPA,
structures associated to the reactions of BnO with DMSO and
in line with the greater HBA ability of HMPA as compared to
HMPA. The calculations utilized newly developed dispersion
correcting potentials (DCPs) along with the B3LYP/6-
59
DMSO. The associated TS structure is about 5 degrees off
−1
3
1+G(2d,2p). The new DCPs correct the erroneous long-
linearity, with an enthalpy barrier of −4.2 kcal mol relative to
(i.e., below) the separated reactants. There are also a number of
secondary interactions between the BnO aromatic ring and
range behavior of the B3LYP functional and enable the method
to very accurately simulate organic systems in which non-
covalent interactions are important. The most stable structure
•
84
HMPA C−H bonds present in these structures. The relatively
•
•
for the prereaction complex between BnO and DMSO is
lower calculated barrier associated with the BnO −HMPA
•
shown in Figure 2a, and involves a strong hydrogen bond
reaction compared to BnO −DMSO is consistent with the
−1
interaction (binding enthalpy of 7.4 kcal mol ) between the
measured rate constants presented in Table 1 that show a
•
•
acidic BnO α-C−H and the oxygen lone pair of DMSO, along
significant increase in rate constant for the reactions of BnO
on going from DMSO to HMPA. The calculated enthalpy vs
with secondary interactions between the DMSO C−H groups
•
•
and the oxygen atom of BnO . General dispersion interactions
reaction coordinate diagrams for the reactions of BnO and
•
•
also contribute to the strong binding of the BnO −DMSO
CumO with DMSO and HMPA are displayed in the
complex. Most importantly, the calculated binding enthalpy of
Supporting Information as Figure S13.
•
•
the BnO −DMSO complex exceeds that of the BnO −
acetonitrile and the acetonitrile−DMSO complexes by 4.0
and 1.3 kcal/mol, respectively, suggesting that formation of the
prereaction complex is an exothermic process. Interestingly,
Taken together, the results of the computational and time-
resolved kinetic studies point toward the great importance of
specific hydrogen-bond interactions in hydrogen abstraction
reactions by primary alkoxyl radicals, where substrate HBA
ability plays a major role.
•
despite the fact that CumO is unable to engage in strong
•
•
hydrogen bonding with the DMSO oxygen, it nevertheless
Large k (BnO )/k (CumO ) ratios have been observed
H H
forms a strongly bound dipole−dipole complex having a
only for hydrogen atom donor substrates characterized by high
•
Figure 2. Predicted hydrogen bonded prereaction complex between BnO and dimethyl sulfoxide (DMSO) (a) and associated transition-state
structure (b) obtained using B3LYP/6-31+G(2d,2p) with dispersion-correcting potentials. Indicated distances and angles are given in angstroms and
degrees. Key: H = white, C = gray, S = yellow, O = red.
1
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The Journal of Organic Chemistry
Featured Article
HBA abilities such as alkylamines, DMSO, TBPO, and HMPA.
where the limiting value of kobs corresponds to the intrinsic rate
•
•
On the other hand, k (BnO )/k (CumO ) ratios <2 have
constant (k ′) for hydrogen atom transfer within the complex,
H
H
H
5
0,85
been observed in the reactions of the two radicals with
substrates characterized by lower HBA abilities such as THF
indicated as k in Scheme 4.
Accordingly, the curved kinetic
2
plot can be evaluated on the basis of eq 2, from which k ′ and
H
H
74
H
34
86
(
β2 = 0.51), aliphatic aldehydes (β = 0.39), and
the preequilibrium constant K = k /k can be obtained.
E 1 −1
2
H
34,74
hydrocarbons (β2 = 0.00),
results that are indicative of a
(
kobs − k ) = K k ′[substrate]/(1 + K [substrate])
(2)
0
E H
E
direct hydrogen abstraction mechanism for the reactions of both
radicals with these substrates.
In this equation, k represents the rate constant for decay of
0
•
In Schemes 2 and 4, k and k represent the rate constants
BnO in the absence of the hydrogen atom donor (DMSO)
1
−1
for the formation and dissociation of the hydrogen-bonded
that, as mentioned above, is mostly due to hydrogen abstraction
from the solvent.
58
prereaction complex and k is the rate constant for intra-
2
molecular hydrogen abstraction within the complex. Based on
A very good fit of the experimental data to eq 2 has been
the discussion outlined above, on the very strong HBA abilities
obtained (Figure 3), leading to the following values of the
of DMSO, TBPO, and HMPA, and on the observation of k /
H
•
k ratios very close to unity for the reactions of BnO with
D
DMSO/DMSO-d and HMPA/HMPA-d , for these substrates
6
18
k ≫ k reasonably applies. Thus, the reaction rate can be
2
−1
expressed in terms of the rate constant for complex formation
•
k as v = k [substrate][BnO ], where k corresponds to the k
1
1
1
H
•
values displayed in Table 1 for the reactions of BnO with the
three substrates.
On the basis of these results, the differences in k observed
H
•
for the reactions of BnO with the different substrates reflect
the role of structural and electronic effects on the formation of
the hydrogen-bonded complex. With the amines, the increase
in k observed on going from acyclic tertiary amines to cyclic
H
and bicyclic amines and diamines, and within an alkylamine
series, on going from the tertiary to the secondary and primary
amine, have been explained on the basis of the accessibility of
the nitrogen lone pair and of the slightly higher HBA ability of
primary and secondary amines as compared to tertiary
5
3
Figure 3. Plot of the observed rate constant (kobs) against [DMSO] for
reaction with the benzyloxyl radical (BnO ), measured in nitrogen-
amines. The rate constants measured for the reactions of
•
•
9
10
the amines with BnO (k between 3.0 × 10 and 1.05 × 10
H
−
1
−1 53−55
saturated acetonitrile solution at T = 25 °C, following the decay of
M
s )
are in all cases higher than those measured with
•
BnO at 460 nm. The solid line represents the fit of the experimental
DMSO, HMPA, and TBPA, despite the lower HBA abilities
displayed by the amines as compared to the latter substrates.
This behavior may be indicative of steric effects reflecting, at
8
data to eq 2. From the regression analysis: K k ′ = 3.3 ± 0.2 × 10
E
H
−1 −1
−1
2
M
s , K = 22.1 ± 2.4 M , r = 0.9932.
E
2
least in part, the sp nature of the oxygen atom of DMSO,
HMPA, and TBPA, where substrate−radical hydrogen bonding
is expected to bring the two species in closer proximity as
compared to the amines, which are characterized by the
intrinsic hydrogen abstraction rate constant and preequilibrium
•
constant for the reaction between BnO and DMSO: k ′ = 1.5
H
7
−1
−1
× 10 s and K = 22.1 M . A saturation behavior has been
also observed for the reaction of BnO with DMSO-d , as
E
3
•
presence of an sp HBA nitrogen center.
Among the rate constants measured for reaction of BnO
6
•
shown in the Supporting Information, Figure S9, from which
7
−1
with substrates characterized by high HBA abilities, the lowest
the following values have been obtained: k ′ = 1.3 × 10 s
D
8
−1 −1
−1
value was measured with DMSO, k = 2.88 × 10 M s ,
and K = 29.0 M . These findings indicate that, at least with
H
E
which is more than 5 times lower than the value measured for
the corresponding reaction with HMPA and at least 1 order of
magnitude lower than the values measured for TBPO and for
the alkylamines. The observation of a relatively low value
suggests that, on the basis of the kinetic scheme displayed in
Scheme 4, by increasing DMSO concentration (i.e., by shifting
the position of the pre-equilibrium), kinetic evidence for the
DMSO, the overall second order rate constant is a composite of
the preequilibrium constant K and of the intrinsic rate constant
E
for hydrogen atom transfer k ′.
H
This kinetic behavior is in full agreement with the
mechanism displayed in Scheme 4, indicating in particular
that the formation of a hydrogen-bonded prereaction complex
•
between BnO and the HBA substrates provides a significant
•
formation of a BnO −DMSO prereaction complex may be
kinetic advantage for the subsequent intracomplex hydrogen
abstraction step. This is clearly revealed through the
comparison of the k and k ′ values measured for the reactions
obtained. For this purpose, the kinetic study of the reaction
•
between DMSO (and DMSO-d ) and BnO has been extended
6
H
H
•
•
4
−1 −1
to significantly higher substrate concentrations as compared to
the experiments shown in the Supporting Information (Figures
S5 and S6) whose results are displayed in Table 1. The
corresponding plot of kobs versus [DMSO] displayed in Figure
of CumO and BnO with DMSO: k = 1.8 × 10 M
s
and
H
7
−1
k ′ = 1.5 × 10 s , respectively. At this stage, we do not have
H
any clear explanation for the very small intramolecular kinetic
deuterium isotope effect observed in these reactions, k ′/k ′ =
H
D
2
shows a significant curvature at substrate concentrations
0.01 M, where kobs appears to approach a limiting (plateau)
1.15, as compared to the value observed for hydrogen
•
≥
abstraction from DMSO and DMSO-d by CumO (k /k =
6
H
D
value. The saturation behavior of k is diagnostic for the
2.0). This behavior may be a consequence of the preorganiza-
tion of the radical-substrate couple in the prereaction complex,
obs
•
formation of a prereaction complex between DMSO and BnO ,
1
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The Journal of Organic Chemistry
Featured Article
as well as the result of the deviation from linearity of the
transition state for the intramolecular reaction (Figure 2b) as
compared to the linear transition state expected for an
Dicumyl peroxide was of the highest commercial quality available
and was used as received. Dibenzyl peroxide was prepared according to
a previously described procedure by reaction of KO with benzyl
2
5
8,89
87
bromide in dry benzene, in the presence of 18-crown-6 ether.
intermolecular reaction. Future experiments are certainly
needed in order to obtain additional information in this respect.
The rate constants for hydrogen abstraction derived from the
Laser Flash Photolysis Studies. LFP experiments were carried
out with a laser kinetic spectrometer using the fourth harmonic (266
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. Nitrogen-saturated acetonitrile solutions of dicumyl
peroxide and dibenzyl peroxide (10 and 8 mM, respectively) were
employed. These concentrations were chosen in order to ensure
prevalent absorption of the 266 nm laser light by the precursor
peroxides. The photochemical stability of the substrates at the laser
excitation wavelength (266 nm) was checked by LFP of acetonitrile
solutions containing substrate concentrations comparable to the
highest concentrations employed in the kinetic experiments. All of
the experiments were carried out at T = 25 ± 0.5 °C under magnetic
stirring. The observed rate constants (kobs) were obtained by averaging
at least three individual values and were reproducible to within 5%.
Second-order rate constants for the reactions of the cumyloxyl and
benzyloxyl radicals with the substrates were obtained from the slopes
of the kobs (measured following the decay of the cumyloxyl and
benzyloxyl radicals visible absorption bands at 490 and 460 nm,
respectively) vs [substrate] plots. Fresh solutions were used for every
substrate concentration. Correlation coefficients were in all cases
>0.992. The given rate constants are the average of at least two
independent experiments, typical errors being ≤10%.
•
kinetic analysis of the reactions of BnO with DMSO and
DMSO-d are very similar to the intramolecular rate constant
6
measured previously for the 1,5-hydrogen abstraction reaction
7
−1 88
of an alkoxyl radical (k = 2.7 × 10 s ), indicating that when
possible, intramolecular hydrogen abstractions by alkoxyl
radicals are very fast processes.
The observation of a larger preequilibrium constant in the
•
reaction of DMSO-d6 with BnO , as compared to the
corresponding reaction with DMSO, is in line with the slightly
larger electron releasing effect of the CD groups as compared
3
to CH mentioned above.
3
In conclusion, the results discussed above on the reactions of
•
•
CumO and BnO with substrates characterized by very high
HBA abilities confirm that substrate−radical hydrogen bonding
can play a very important role in hydrogen abstraction reactions
by alkoxyl radicals. With all substrates, very large increases in
•
•
reactivity were observed on going from CumO to BnO , as
•
•
quantified by the k (BnO )/k (CumO ) ratios that vary from
6 for the reactions with HMPA to 1.6 × 10 for those with
DMSO. The reactions with BnO proceed through the
formation of hydrogen bonded substrate-radical prereaction
complexes, followed by hydrogen abstraction within the
H
H
4
8
•
Calculations. All calculations were performed using the Gaussian-
9
0
91
92
93
09 package of programs utilizing the B3 LYP and B3P86
approaches implemented therein. The B3LYP calculations utilized a
new family of dispersion-correcting potentials that allow that
functional to accurately predict noncovalent interactions. Additional
information on the B3LYP dispersion-correcting potentials is available
at www.ualbert.ca/∼gdilabio.
•
complex. With CumO , which cannot act as a HBD, the
reactions have been described in all cases in terms of a direct
hydrogen abstraction mechanism, that is, without the formation
of a strongly bound prereaction complex. Strong support for
this mechanistic picture is provided by the results of
computational studies and by the observation of sizable kinetic
deuterium isotope effects in the reactions of DMSO and
ASSOCIATED CONTENT
Supporting Information
■
*
S
•
Plots of kobs vs substrate concentration for the reactions of
HMPA with CumO and of kinetic deuterium isotope effects
•
•
•
CumO and BnO and details of the calculations. This material
is available free of charge via the Internet at http://pubs.acs.org.
close to unity for the corresponding reactions with BnO .
Kinetic evidence for the formation of a prereaction complex has
•
also been obtained for the reactions of BnO with DMSO and
AUTHOR INFORMATION
Corresponding Author
E-mail: Gino.DiLabio@nrc.ca; bietti@uniroma2.it.
DMSO-d . These results provide quantitative information on
■
*
6
the very important role played by specific substrate-radical
interactions in these processes, showing in particular that with
•
BnO (and with other primary and secondary alkoxyl radicals)
Notes
the presence of a strong HBA site in the hydrogen atom donor
promotes complex formation and preorganizes the reactants for
hydrogen abstraction leading to dramatic rate enhancements as
compared to the corresponding reactions of radicals that
cannot act as HBDs. The implications of these findings are
currently under investigation in our laboratory.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Ministero dell’Istruzione dell’Uni-
■
versita
̀
e della Ricerca (MIUR) is gratefully acknowledged. We
thank Prof. Lorenzo Stella for the use of a LFP equipment.
A very important aspect of this study is that the rate
•
constants measured for the reactions of CumO with DMSO
DEDICATION
■
and HMPA provide, for the first time, a quantitative evaluation
of the hydrogen abstraction reactivity of these widely employed
compounds.
This paper is dedicated to Prof. Steen Steenken on the occasion
of his 75th birthday.
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•
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(
82
at sulfur. Along this line, a reviewer has pointed out that the
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•
difference in reactivity observed between CumO and BnO in their
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dx.doi.org/10.1021/jo3019889 | J. Org. Chem. 2012, 77, 10479−10487