Hydrogen abstraction from cyclic amines by the cumyloxyl and benzyloxyl radicals. the role of stereoelectronic effects and of substrate/radical hydrogen bonding

Article abstract of DOI:10.1021/jo3015352

A kinetic study on the hydrogen abstraction reactions from cyclic amines and diamines (pyrrolidines, piperidines, morpholines, and piperazines) by the cumyloxyl (CumO^?) and benzyloxyl (BnO^?) radicals was carried out. The reactions with CumO^? were described in all cases as direct hydrogen abstractions. The differences in the hydrogen abstraction rate constant (k_H) were explained in terms of the different number of abstractable hydrogen atoms, the operation of stereoelectronic effects, and, with the morpholines, on the basis of polar effects. Significantly higher k_H values were measured for the reactions of the amines with BnO^?. This behavior was explained on the basis of a mechanism that proceeds through the rate-determining formation of a hydrogen bonded pre-reaction complex between the radical α-C-H and the nitrogen lone pair followed by hydrogen abstraction within the complex. A decrease in k_H was observed going from secondary to tertiary amines and, with tertiary amines, on increasing steric hindrance at nitrogen, pointing toward the important role of steric and electronic effects on pre-reaction complex formation. These results expand previous findings contributing to a detailed mechanistic description of the reactions of alkoxyl radicals with amines, showing that structural effects in both the substrate and the radical can play a dramatic role and providing new information on the role of substrate/radical interactions on these processes.

Full text of DOI:10.1021/jo3015352

Article
pubs.acs.org/joc
Hydrogen Abstraction from Cyclic Amines by the Cumyloxyl and
Benzyloxyl Radicals. The Role of Stereoelectronic Effects and of
Substrate/Radical Hydrogen Bonding
Michela Salamone, Roberto Martella, and Massimo Bietti*
Dipartimento di Scienze e Tecnologie Chimiche, Universita
S Supporting Information
̀
″Tor Vergata″, Via della Ricerca Scientifica, 1 I-00133 Rome, Italy
*
ABSTRACT: A kinetic study on the hydrogen abstraction reactions from cyclic
amines and diamines (pyrrolidines, piperidines, morpholines, and piperazines) by the
•
•
cumyloxyl (CumO ) and benzyloxyl (BnO ) radicals was carried out. The reactions
•
with CumO were described in all cases as direct hydrogen abstractions. The
differences in the hydrogen abstraction rate constant (k ) were explained in terms of
H
the different number of abstractable hydrogen atoms, the operation of stereoelectronic
effects, and, with the morpholines, on the basis of polar effects. Significantly higher k
values were measured for the reactions of the amines with BnO . This behavior was explained on the basis of a mechanism that
H
•
proceeds through the rate-determining formation of a hydrogen bonded pre-reaction complex between the radical α-C−H and
the nitrogen lone pair followed by hydrogen abstraction within the complex. A decrease in k was observed going from secondary
H
to tertiary amines and, with tertiary amines, on increasing steric hindrance at nitrogen, pointing toward the important role of
steric and electronic effects on pre-reaction complex formation. These results expand previous findings contributing to a detailed
mechanistic description of the reactions of alkoxyl radicals with amines, showing that structural effects in both the substrate and
the radical can play a dramatic role and providing new information on the role of substrate/radical interactions on these
processes.
INTRODUCTION
Scheme 1
■
Alkoxyl radicals are an important class of oxygen centered
radicals that are involved in a variety of chemical and biological
1
−4
processes. Hydrogen abstraction represents one of the most
important reactions of these radicals, and accordingly, a large
number of studies have been devoted to the mechanistic
5
−15
investigation of these processes.
Among the hydrogen atom
significantly higher BDE of a N−H bond as compared to α-C−
H bonds.
donors employed in these studies, aliphatic amines have
attracted great interest. These substrates are characterized by
electron-rich α-C−H bonds and undergo hydrogen abstraction
In order to obtain information on the role of alkoxyl radical
structure on these processes, we have recently carried out
detailed time-resolved kinetic studies in acetonitrile solution on
the hydrogen abstraction reactions from primary, secondary,
16
by electron-poor radicals such as alkoxyls, with relatively high
8
−1 −1
rate constants (kH ∼ 10 M
s
at room temperature in
acetonitrile solution). Accordingly, a rather detailed description
of the role of structural and solvent effects on hydrogen
abstraction reactions from alkylamines by alkoxyl radicals has
been provided, limited however to the reactions of two tertiary
•
and tertiary alkylamines by CumO with comparison to the
•
•
26−28
primary alkoxyl radical benzyloxyl (PhCH O , BnO ).
2
With all the amines investigated, an increase in reactivity has
•
•
•
•
been observed on going from CumO to BnO , as measured by
alkoxyl radicals: the tert-butoxyl ((CH ) CO , tBuO ) and
3
3
•
•
•
•
17−25
the rate constant ratios (k (BnO )/k (CumO ) that varied
H H
cumyloxyl (PhC(CH ) O , CumO ) radicals.
These
3
2
between 2.8 for the reactions of the two radicals with a
relatively hindered amine such as triisobutylamine (TIBA), and
3380 for the reactions with tert-octylamine (TOA). Quite
studies have shown that hydrogen abstraction reactions from
the α-C−H bonds of alkylamines are generally entropy
1
9
controlled, and that the reaction is most rapid when the α-
C−H bond being broken can be eclipsed with the nitrogen lone
pair, indicating that stereoelectronic effects play an important
•
•
importantly, the highest (k (BnO )/k (CumO ) ratios have
H
H
been observed with amines that undergo relatively slow
•
1
9,20,24
hydrogen abstraction by CumO , namely 1,4-diazabicyclo-
role in these reactions.
With primary and secondary
[
2
2,2,2]octane (DABCO), 1-azabicyclo[2,2,2]octane (ABCO),
,2,6,6-tetramethylpiperidine (TMPPD), and TOA
alkylamines, competition between α-C−H and N−H abstrac-
tion to give α-aminoalkyl and aminyl radicals, respectively, is
20−24
generally observed as described in Scheme 1.
The greater importance of the former pathway as compared
to the latter one has been explained on the basis of the
Received: July 20, 2012
Published: September 7, 2012
©
2012 American Chemical Society
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The Journal of Organic Chemistry
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•
•
(
(k (BnO )/k (CumO ) = 1094, 2027, 1182, and 3380,
pyrrolidine (PRD), N-methylpyrrolidine (MPRD), N-tert-
butylpyrrolidine (BPRD), piperidine (PPD), N-methylpiper-
idine (MPPD), N-tert-butylpiperidine (BPPD), morpholine
(MPH), N-methylmorpholine (MMPH), piperazine (PPZ),
and 1,4-di-tert-butylpiperazine (DBPPZ), whose structures are
displayed in Chart 1. Also included are the structures of the
H
H
respectively). The lower rate constants measured for the
reactions of CumO with ABCO and DABCO have been
explained on the basis of a stereoelectronic effect, because in
these substrates, the α-C−H bonds are held with a dihedral
angle of ca. 60°, in a conformation that does not allow efficient
•
1
9,20,24
overlap with the nitrogen lone pair.
With TMPPD and
TOA, hydrogen abstraction can only occur from the N−H
Chart 1
bond, a feature that, as mentioned above, accounts for the low
•
k values measured for their reactions with CumO (k = 3.13
H
H
6
6
−1 −1
26
×
10 , and 1.34 × 10 M s , respectively). Along these
lines, the very high (k (BnO )/k (CumO ) ratios observed for
•
•
H
H
the reactions of ABCO, DABCO, TMPPD, and TOA clearly
indicate that stereoelectronic effects and N−H BDEs play a
•
negligible role in the reactions of these substrates with BnO .
The large differences in reactivity observed for the reactions
•
•
of CumO and BnO with alkylamines have been explained on
the basis of two different mechanisms. The reactions with
•
CumO have been described in terms of a direct hydrogen
abstraction mechanism, indicative of a reaction that proceeds
through the interaction of the radical center with the amine α-
18−24
C−H and/or N−H bond, in line with previous studies,
described in Scheme 2 for a generic tertiary amine.
as
Scheme 2
previously investigated substrates 2,2,6,6-tetramethylpiperidine
(
1
TMPPD), 1,2,2,6,6-pentamethylpiperidine (PMPPD), and
,4-dimethylpiperazine (DMPPZ).
26,27
RESULTS
■
•
•
•
The reactions of BnO have been instead described in terms
of a mechanism that proceeds through the rate determining
The reactions of CumO and BnO with the amines displayed
in Chart 1 have been studied using the laser flash photolysis
(LFP) technique. The alkoxyl radicals have been generated by
266 nm LFP of nitrogen-saturated acetonitrile solutions (T =
25 °C) containing the parent peroxides, according to eq 1.
•
formation of a pre-reaction complex, where the BnO α-C−H
engages in hydrogen bonding with the amine lone pair,
followed by hydrogen abstraction within the complex (Scheme
3
, paths a−b). Evidence in favor of this mechanistic picture has
26,28
also been provided through computational studies.
Scheme 3
•
•
CumO and BnO are characterized by a broad absorption
band in the visible region of the spectrum that, in acetonitrile
29,30
solution, is centered at 485 and 460 nm, respectively.
Under the experimental conditions employed, the most
•
important decay pathway of CumO is represented by C−
1
2,29
•
CH β-scission,
while the decay of BnO is mainly
31
3
attributed to hydrogen abstraction from the solvent.
The kinetic studies have been carried out by LFP in
•
acetonitrile solution following the decay of the CumO and
BnO visible absorption bands at 490 and 460 nm, respectively,
•
Efficient complex formation is possible only for relatively
unhindered amines. With TIBA, steric hindrance prevents the
formation of a sufficiently stable complex, and its reaction with
as a function of the amine concentration. The reactions of
•
MPPD and MMPH with CumO have also been studied in
•
BnO has been described as a direct hydrogen abstraction
2,2,4-trimethylpentane (isooctane) solution.
Excellent linear relationships have been obtained when the
28
(
Scheme 3, path c, R = CH(CH ) ).
3
2
In view of the relevance of these processes, and in order to
observed rate constants (k ) have been plotted against
obs
develop a deeper mechanistic understanding of the role of
structural effects on the hydrogen abstraction reactions from
amines by alkoxyl radicals, in particular for what concerns the
role of stereoelectronic effects and of substrate−radical
hydrogen bond interactions, we have extended the kinetic
studies to the reactions of CumO and BnO with a series of
secondary and tertiary cyclic amines and diamines, namely,
substrate concentration. The second-order rate constants for
hydrogen abstraction from the substrates (k ) by the alkoxyl
H
radicals have been obtained from the slopes of these plots. As
an example, Figure 1 shows the plots of k vs [PPD] for the
obs
•
•
reactions of this amine with CumO (filled circles) and BnO
•
•
(open circles) for measurements carried out in acetonitrile
solution at T = 25 °C.
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The Journal of Organic Chemistry
Article
•
•
experimental conditions for the reactions of CumO and BnO
with TMPPD, PMPPD, and DMPPZ.
26
27
DISCUSSION
■
•
Starting from the reactions of CumO , the kinetic data
displayed in Table 1 show that, within the pyrrolidine,
piperidine, and piperazine series, the k values vary in a
H
8
−1 −1
limited range, between 1.07 × 10 M
(
(
s
for piperidine
for N-tert-butylpyrrolidine
BPRD). In this comparison, it is, however, important to take
8
−1 −1
PPD) and 3.0 × 10 M
s
into account that these substrates are characterized by different
numbers of α-C−H bonds, i.e., of the hydrogen atoms that are
17−25
known to be preferentially abstracted by alkoxyl radicals.
With PRD and PPD, our measured k values for reaction
H
•
with CumO are in good agreement with the literature values
•
7
for the corresponding reactions with tBuO (k = 9.5 × 10 and
H
7
−1 −1
7
.9 × 10 M s , respectively, at T = 22 °C, in benzene/di-
24
Figure 1. Plots of the observed rate constant (kobs) against
•
[
piperidine] for the reactions of the cumyloxyl radical (CumO , filled
tert-butylperoxide 1:2), in line with the very similar hydrogen
•
•
circles) and benzyloxyl radical (BnO , open circles), measured in
abstraction reactivities generally displayed by tBuO and
•
20,32−34
nitrogen-saturated acetonitrile solution at T = 25 °C by following the
CumO .
•
•
decay of CumO and BnO at 490 and 460 nm, respectively. From the
Lower kH values have been measured for the reactions of
•
5 −1
linear regression analysis: CumO + PPD: intercept = 8.13 × 10 s ,
k = 1.06 × 10 M s , r = 0.9975; BnO + PPD: intercept = 9.60 ×
0 s , k = 7.04 × 10 M s , r = 0.9982.
•
CumO with morpholine (MPH) and N-methylmorpholine
8
−1 −1
2
•
H
1
MMPH) (kH = 5.0 × 107 and 4.32 × 10
7
−1
−1
(
M
s ,
5
−1
9
−1 −1
2
H
respectively). These values are between 2 and 3 times lower
than the values measured for the corresponding reactions of
PPD and N-methylpiperidine (MPPD), where the observed
decrease in reactivity clearly reflects the replacement of the
Additional plots for the hydrogen abstraction reactions by
•
•
CumO and BnO from the other amines are displayed in the
Supporting Information (Figures S1−S20). All the kinetic data
thus obtained are collected in Table 1 together with the
pertinent k (BnO )/k (CumO ) ratios. Also included in Table
are the rate constants obtained previously under analogous
CH in position 4 of the piperidine ring with an oxygen atom
2
(see later).
•
•
Previous studies on the hydrogen abstraction reactions from
H
H
•
•
1
tertiary amines by tBuO and CumO have clearly shown that
these reactions can be described in terms of the direct hydrogen
abstraction mechanism displayed in Scheme 2, with the
reaction that is most rapid when the α-C−H bond is collinear
with the nitrogen lone pair, thus allowing the best orbital
Table 1. Second-Order Rate Constants (k ) for the
Reactions of the Cumyloxyl (CumO ) and Benzyloxyl
BnO ) Radicals with Secondary and Tertiary Cyclic Amines
and Diamines
H
•
•
(
1
9,20,24
overlap.
This overlap determines a decrease in the α-C−
H BDE and a corresponding stabilization of the α-aminoalkyl
radical formed after hydrogen abstraction. Along these lines, a
direct hydrogen abstraction mechanism can also be applied for
k /M− s−1
1
a
H
•
k(BnO )/
b
CumO•
BnO•
•
substrate
k(CumO )
•
the description of the reactions of CumO with the cyclic
8
9
PRD
1.24 ± 0.05 × 10
1.91 ± 0.01 × 10
3.0 ± 0.1 × 10
1.07 ± 0.01 × 10
1.22 ± 0.04 × 10
.38 ± 0.04 × 10
1.26 ± 0.05 × 10
3.13 ± 0.02 × 10
1.71 ± 0.02 × 10
5.0 ± 0.2 × 10
4.32 ± 0.06 × 10
8.03 ± 0.03 × 10
6.2 ± 0.2 × 10
65
32
amines and diamines displayed in Chart 1, where the
differences in reactivity observed for the reactions with the
pyrrolidines, piperidines, and piperazines can be conveniently
explained on the basis of the different number of abstractable
hydrogen atoms and of the contribution of stereoelectronic
effects.
8
9
MPRD
BPRD
PPD
8
9
9
9
4.05 ± 0.09 × 10
7.00 ± 0.04 × 10
5.61 ± 0.08 × 10
13.5
65
8
8
8
8
6
8
MPPD
46
c
2
9
BPPD
3.1 ± 0.3 × 10
25
1182
25
In the pyrrolidine series, the increase in k observed on going
H
d
9
TMPPD
3.7 ± 0.1 × 10
from PRD to MPRD reasonably reflects the increased number
of α-C−H bonds (4 for PRD and 7 for MPRD), taking in
particular into account that with tertiary alkoxyl radicals
significantly higher rate constants have been measured for
hydrogen abstraction reactions from α-C−H bonds as
e
9
9
PMPPD
MPH
4.26 ± 0.07 × 10
5.69 ± 0.05 × 10
7
114
118
7
9
MMPH
5.1 ± 0.2 × 10
7
c
9.6 ± 0.1 × 10
8
8
8
9
PPZ
2.26 ± 0.01 × 10
1.16 ± 0.04 × 10
1.32 ± 0.02 × 10
9.5 ± 0.1 × 10
42
69
44
8
−1 −1
compared to N−H bonds (k
= 1.71 × 10 M s , for
C−H
e
9
DMPPZ
DBPPZ
8.0 ± 0.1 × 10
•
the reaction of CumO with 1,2,2,6,6-pentamethylpiperidine
PMPPD), as compared to kN−H = 3.13 × 10 M
corresponding reaction with 2,2,6,6-tetramethylpiperidine
9
27
5.8 ± 0.1 × 10
6
−1 −1
(
s
for the
a
Measured in N -saturated acetonitrile solution at T = 25 °C by 266
26
2
(
TMPPD); see Table 1). Accordingly, when corrected for
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
the decay of the CumO or BnO visible absorption bands at 490 and
60 nm, respectively. Average of at least two determinations. For
substrate structures, see Chart 1. Measured in isooctane solution.
Ref 26. Ref 27.
the different number of abstractable α-C−H hydrogens, very
similar rate constant values are observed for the reactions of
[
obs
•
7
•
•
PRD and MPRD with CumO : k
= 3.1 × 10 and 2.7 ×
H(corr)
7
−1 −1
b
1
0 M s , respectively.
Quite interestingly, an increase in k has been observed on
4
c
H
d
e
going from PRD and MPRD to BPRD (where hydrogen
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abstraction can only occur from the ring carbons), despite the
same number of α-C−H bonds in PRD and BPRD, and of the
decreased number of α-C−H bonds on going from MPRD to
BPRD. These results show that, as compared to PRD and
MPRD, BPRD is activated toward hydrogen abstraction by
Scheme 4
•
CumO , indicating a peculiar role for the tert-butyl substituent
and pointing toward the operation of stereoelectronic effects. It
is reasonable to propose that in BPRD the bulkyness of the tert-
butyl group favors a conformation that allows a higher degree
of overlap between an α-C−H bond and the nitrogen lone pair,
as compared to PRD and MPRD, leading to the observed
increase in rate constant.
Quite interestingly, the observation of significantly higher kH
values for the reactions of BPPD and DBPPZ with CumO as
•
compared to those measured for the corresponding reactions of
6
6
ABCO and DABCO (for which k = 3.7 × 10 and 9.6 × 10
H
−1 −1
20
As compared to the pyrrolidine series, smaller differences in
reactivity have been observed for the piperidine and piperazine
M
s , respectively), where as mentioned above the α-C−H
bonds are held in a conformation that does not allow efficient
1
9,20,24
series. Almost identical k values have been measured for the
H
overlap with the nitrogen lone pair,
clearly indicates that,
•
reactions of CumO with PPD, MPPD, and BPPD, whereas a
despite the presence of bulky substituents on nitrogen, the six-
membered ring of these substrates is still sufficiently flexible to
achieve efficient overlap between the equatorial α-C−H bonds
and the nitrogen lone pair.
decrease in kH has been observed on going from PPZ and
DMPPZ to DBPPZ. These results can be reasonably explained
on the basis of the contribution of the two factors discussed
above (number of abstractable hydrogen atoms and stereo-
electronic effects) within these series, where however the
relative importance of these contributions is very difficult to
establish. On a per hydrogen basis, PPD and PPZ undergo
hydrogen abstraction from the ring α-C−H bonds with almost
−1
As mentioned above, among the different substrates the
lowest kH values have been measured for the reactions of
•
CumO with MPH and MMPH. Replacement of the CH
2
group in position 4 of the piperidine ring with oxygen leads to a
substantial decrease in basicity (the protonated forms of MPH
7
7
identical rate constants (k
= 2.7 × 10 and 2.8 × 10 M
H(corr)
and PPD are characterized by pK values in DMSO (water) of
a
−1
36
s , respectively). Comparison between the k value measured
H
9.15 (8.49) and 10.85 (11.12), respectively), and is also
for PMPPD, that as mentioned above can only undergo
expected to decrease the electron density at the nitrogen α-C−
H bonds. Along this line, the decrease in hydrogen abstraction
reactivity observed on going from the piperidines to the
morpholines can be reasonably explained on the basis of polar
26
hydrogen abstraction from the N-methyl group, and those
measured for MPPD and DMPPZ, clearly shows a decrease in
hydrogen abstraction reactivity from the N-methyl groups on
going from the former substrate to the latter ones. For PMPPD
and DMPPZ, this behavior has been previously explained in
terms of the operation of stereoelectronic effects. Calculations
have shown that it is easier for PMPPD than DMPPZ to orient
its N-methyl α-C−H bond so that it is properly aligned with
the nitrogen lone pair in the most suited conformation for
•
effects, because the electrophilic radical CumO will abstract an
hydrogen atom more rapidly from the former substrates as
16
compared to the latter ones.
We have also investigated whether these differences in
reactivity may be a consequence of the interaction of the
solvent with the oxygen lone pairs of the morpholine substrates.
On the basis of the hypothesis that this interaction may
influence the conformational equilibrium leading to a decrease
in reactivity of the morpholines as compared to the
corresponding piperidines, we have studied the reactions of
2
7
hydrogen atom abstraction. A similar explanation will
reasonably account for the decrease in reactivity observed on
going from PMPPD to MPPD.
Comparison between the k values measured for PMPPD,
H
•
PPD, MPPD, PPZ, and DMPPZ also indicates that the
presence of N-methyl groups leads to a significant decrease in
the reactivity of the ring α-C−H bonds. With PPD, MPPD,
PPZ, and DMPPZ, optimal overlap between the ring α-C−H
bonds and the nitrogen lone pair requires a certain degree of
ring distortion, and the attainment of such conformation is
expected to be energetically more costly for MPPD and
DMPPZ as compared to PPD and PPZ.
CumO with MPPD and MMPH in the noncoordinating
solvent isooctane. The kinetic data displayed in Table 1 show a
very similar behavior for the two substrates, with comparable
increases in the k value on going from acetonitrile to isooctane
H
(kH(isooctane)/kH(MeCN) = 1.95 and 2.22, for MPPD and MMPH,
respectively). These results clearly indicate that the hypothesis
of a specific solvent effect on the conformational equilibria of
the morpholine substrates can be discarded. A similar kinetic
Along these lines, the very small increase in k observed in
effect has been previously observed for the corresponding
H
•
the piperidine and piperazine series on going from the N-
methyl substituted substrates to the N-tert-butyl substituted
ones indicates that, also with six-membered ring substrates, the
presence of N-tert-butyl substituents activates the ring α-C−H
reactions of CumO with triethylamine (kH(isooctane)/kH(MeCN)
1.45).
=
1
7,27
This behavior has been explained on the basis of a
hydrogen bond interaction between the nitrogen center and the
solvent that decreases the degree of overlap between the α-C−
H bond and the nitrogen lone pair in the transition state for
hydrogen abstraction leading to a decrease in reactivity.
Hydrogen bonding can take place only with acetonitrile that
is a relatively weak hydrogen bond donor (HBD), as measured
•
bonds toward hydrogen abstraction by CumO . An explanation
for this behavior can be put forward on the basis of the well-
known stretching of six-membered rings induced by the
35
presence of bulky substituents, that, as compared to the N-
methyl substituted substrates, makes easier the attainment of
the most suited conformation for hydrogen abstraction, as
shown in Scheme 4 (R = Me, t-Bu), where ring stretching
determined by the replacement of the N-methyl by tert-butyl is
expected to increase the degree of overlap between the
equatorial α-C−H bonds and the nitrogen lone pair.
by Abraham’s α2H parameter (α2 = 0.09), and not with
isooctane for which α2H = 0.00. The same explanation
reasonably holds for the kinetic solvent effects observed in
H
37
•
the reactions of CumO with MPPD and MMPH.
The data displayed in Table 1 show that the kH values
•
measured for the reactions of BnO with the cyclic amines and
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diamines are in all cases between 1 and 2 orders of magnitude
higher than those measured for the corresponding reactions of
forward in the present study. The replacement of hydrogen by
an alkyl group increases the steric hindrance around the
nitrogen atom, decreasing in the same time the substrate HBA
ability (as measured by Abraham’s β2H parameter: β2H = 0.69−
0.73 for primary and secondary amines, and 0.58−0.62 for
•
CumO , as quantitatively indicated by the rate constant ratios
•
•
(
k (BnO )/k (CumO ) that vary between 13.5 for the
H H
reactions with BPRD and 118 for the reactions with MMPH.
These differences are similar to those observed previously for
the reactions of these two radicals with a variety of
38
tertiary amines (0.67 for triethylamine)). Both factors will
affect rate and efficiency of pre-reaction complex formation
contributing to the observed kinetic behavior.
2
6−28
alkylamines,
and can be explained accordingly, on the
•
basis of the two mechanisms described in Schemes 2 and 3. As
mentioned above, the reactions of the cyclic amines and
The importance of steric effects in the reactions BnO with
the amines is also evidenced by the slightly higher k values
H
•
diamines with CumO can be described in all cases in terms of
measured for the reactions of the unsubstituted and N-alkyl
substituted pyrrolidines, piperidines, and piperazines as
the direct hydrogen abstraction mechanism shown in Scheme 2
for a generic tertiary amine.
compared to the values measured for the corresponding
•
26,27
The reactions of BnO proceed instead through the rate-
reactions of secondary and tertiary acyclic alkylamines,
in
determining formation of a hydrogen-bonded substrate−radical
pre-reaction complex between the nitrogen lone pair and the
radical α-C−H wherein fast hydrogen abstraction occurs, as
described in Scheme 5 for BPPD, in close analogy to the
mechanism described above for the reactions of BnO with
acyclic alkylamines (Scheme 3, paths a−b).
line with the observation that the nitrogen lone pairs of these
cyclic amines are expected to be more easily accessible to BnO
than those of the acyclic amines.
The slight decrease in reactivity observed on going from the
piperidines to the morpholines can again be explained on the
basis of the inductive effect of the oxygen atom. Replacement of
•
•
a CH group with an oxygen atom decreases the substrate HBA
2
Scheme 5
ability leading to lower rate constant for pre-reaction complex
formation for the morpholines as compared to the piperidines.
In conclusion, the results presented above provide new
information on the role of structural and electronic effects in
both the radical and the substrate on hydrogen abstraction
reactions from amines by alkoxyl radicals, expanding previous
findings and leading to a very detailed mechanistic picture for
•
•
•
the reactions of CumO and BnO . The reactions of CumO
with the cyclic amines and diamines can be described in all
cases on the basis of a direct hydrogen atom abstraction
mechanism where stereoelectronic effects play an important
•
role. With BnO , the reactions can be instead described in
terms of the rate determining formation of a hydrogen-bonded
substrate−radical pre-reaction complex followed by fast hydro-
gen abstraction. In these reactions, a major role is played by
substrate HBA ability and by the accessibility of the nitrogen
lone pair.
In Scheme 5, k and k represent the rate constants for the
formation and dissociation of the hydrogen-bonded pre-
1
−1
reaction complex, while k is the rate constant for hydrogen
2
abstraction within the complex. On the basis of our previous
•
26−28
studies on the reactions of BnO with alkylamines,
also for
EXPERIMENTAL SECTION
the cyclic amines and diamines employed in the present study
■
k ≫ k reasonably applies. Accordingly, the reaction rate can
Materials. Spectroscopic-grade acetonitrile and 2,2,4-trimethylpen-
tane (isooctane) were used in the kinetic experiments. Pyrrolidine
2
−1
•
be expressed as v = k [substrate][BnO ], where the rate
1
(
PRD), N-methylpyrrolidine (MPRD), piperidine (PPD), N-methyl-
piperidine (MPPD), morpholine (MPH), N-methylmorpholine
MMPH), and piperazine (PPZ) were of the highest commercial
constant for complex formation k corresponds to the k values
1
H
•
displayed in Table 1 for the reactions of BnO with the three
substrates. These results provide additional information on the
important role played by specific substrate−radical interactions
(
quality available (≥99%) and were further purified prior to use by
filtration over neutral alumina. The purity of the substrates was
checked by GC prior to the kinetic experiments and was in all cases
•
in these processes, suggesting in particular that with BnO the
presence of a relatively strong hydrogen bond acceptor (HBA)
site in the hydrogen atom donor promotes complex formation
and preorganizes the reactants for hydrogen abstraction leading
to large rate enhancements as compared to the corresponding
>99.5%.
N-tert-Butylpyrrolidine (BPRD), N-tert-butylpiperidine (BPPD),
and 1,4-di-tert-butylpiperazine (DBPPZ) were prepared according to
previously described procedures. BPRD and BPPD were prepared by
reaction of tert-butylamine with 1,4-dibromobutane and 1,5-
dibromopentane, respectively, in absolute ethanol in the presence of
•
reactions of radicals that cannot act as HBDs such as CumO .
In the different series, a decrease in k is observed in all cases
H
3
9
potassium carbonate. DBPPZ was prepared by a slight modification
of this procedure, by reaction of N,N′-di-tert-butylethylenediamine
with 1,2-dibromoethane, where ethanol was replaced by DMSO.
on going from the secondary to the tertiary amines, and, within
the tertiary amines, on going from the N-methyl to the N-tert-
butyl substituted amine, i.e., by increasing the steric hindrance
of the substituent. A similar trend has been observed for the
1
BPRD, BPPD, and DBPPZ were identified by H NMR, showing
39,40
spectral data in full agreement with the literature.
•
reactions of acyclic alkylamines with BnO , where a decrease in
1
H NMR (CDCl ). BPRD: δ 2.64 (m, 4H), 1.77 (m, 4H), 1.09 (s,
3
k has been observed along different series on going from the
H
9H). BPPD: δ 2.51 (m, 4H), 1.58 (m, 4H), 1.43 (m, 2H), 1.06 (s,
26
primary to the secondary and tertiary amine. This behavior
has been explained on the basis of the combination of steric and
electronic effects, and a common explanation can be put
9
H). DBPPZ: δ 2.56 (s, 4H, CH ), 1.00 (s, 9H).
2
The purity of BPRD, BPPD, and DBPPZ used in the kinetic
experiments was checked by GC and was in all cases >99.5%.
8
560
dx.doi.org/10.1021/jo3015352 | J. Org. Chem. 2012, 77, 8556−8561

The Journal of Organic Chemistry
Article
Dicumyl peroxide was of the highest commercial quality available
and was used as received. Dibenzyl peroxide was prepared in small
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2
the presence of 18-crown-6 ether, according to a previously described
3
0,41
procedure.
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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 solutions of dicumyl and dibenzyl
peroxide (10 and 8 mM, respectively) were employed. These
concentrations were chosen in order to ensure, in the presence of
amines, prevalent absorption of the 266 nm laser light by the precursor
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within 5%.
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ASSOCIATED CONTENT
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■
*
S
Supporting Information
Plots of k vs amine concentration for the reactions of CumO•
(26) Salamone, M.; DiLabio, G. A.; Bietti, M. J. Am. Chem. Soc. 2011,
obs
•
133, 16625−16634.
27) Salamone, M.; DiLabio, G. A.; Bietti, M. J. Org. Chem. 2011, 76,
264−6270.
28) Salamone, M.; Anastasi, G.; Bietti, M.; DiLabio, G. A. Org. Lett.
and BnO . This material is available free of charge via the
(
6
(
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: bietti@uniroma2.it
■
2011, 13, 260−263.
(29) Baciocchi, E.; Bietti, M.; Salamone, M.; Steenken, S. J. Org.
Chem. 2002, 67, 2266−2270.
*
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The authors declare no competing financial interest.
(31) Konya, K. G.; Paul, T.; Lin, S.; Lusztyk, J.; Ingold, K. U. J. Am.
Chem. Soc. 2000, 122, 7518−7527.
ACKNOWLEDGMENTS
Financial support from the Ministero dell’Istruzione dell’Uni-
■
(32) Valgimigli, L.; Banks, J. T.; Ingold, K. U.; Lusztyk, J. J. Am.
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(
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