Competitive Hydrogen Atom Transfer to Oxyl- and Peroxyl Radicals in the Cu-Catalyzed Oxidative Coupling of N-Aryl Tetrahydroisoquinolines Using tert-Butyl Hydroperoxide

Article abstract of DOI:10.1021/acscatal.6b00944

The question of whether hydrogen atom transfer (HAT) or electron transfer (ET) is the key step in the activation of N-aryl tetrahydroisoquinolines in oxidative coupling reactions using CuBr as catalyst and tert-butyl hydroperoxide (tBuOOH) has been invest

Full text of DOI:10.1021/acscatal.6b00944

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Article
Competitive Hydrogen Atom Transfer to Oxyl- and Peroxyl
Radicals in the Cu-Catalyzed Oxidative Coupling of N-Aryl
Tetrahydroisoquinolines Using tert-Butyl Hydroperoxide
Esther Böß, Larry Michael Wolf, Santanu Malakar, Michela
Salamone, Massimo Bietti, Walter Thiel, and Martin Klussmann
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00944 • Publication Date (Web): 11 Apr 2016
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Competitive Hydrogen Atom Transfer to Oxyl- and Peroxyl Radicals
in the Cu-Catalyzed Oxidative Coupling of N-Aryl Tetrahydroisoquin-
olines Using tert-Butyl Hydroperoxide
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Esther Boess,† Larry M. Wolf,† Santanu Malakar,†,§ Michela Salamone,‡ Massimo Bietti,*,‡
Walter Thiel*,† and Martin Klussmann*,†
†Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
‡Dipartimento di Scienze e Tecnologie Chimiche Università "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy
§Present address: Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
ABSTRACT: The question of whether hydrogen atom transfer (HAT) or electron transfer (ET) is the key step in the activa-
tion of N-aryl tetrahydroisoquinolines in oxidative coupling reactions using CuBr as catalyst and tert-butyl hydroperoxide
(tBuOOH) has been investigated. Strong indications for a HAT mechanism were derived by using different para-substituted
N-aryl tetrahydroisoquinolines, showing that electronic effects play a minor role in the reaction. Hammett plots of the Cu-
catalyzed reaction, a direct time-resolved kinetic study with in situ generated cumyloxyl radicals, as well as density func-
tional calculations gave essentially the same results. We conclude from these results and from kinetic isotope effect exper-
iments that HAT is mostly mediated by tert-butoxyl radicals and only to a lesser extent by tert-butylperoxyl radicals, in
contrast to common assumptions. However, reaction conditions affect the competition between these two pathways, which
can significantly change the magnitude of kinetic isotope effects.
ever, some debate still exists over the exact mode of activa-
tion of the amine. Here we present results from kinetic and
theoretical studies addressing this question.
KEYWORDS: oxidative coupling, C-H functionalization,
radicals, reaction mechanism, hydrogen atom transfer,
kinetics, kinetic isotope effect
[catalyst]
oxidant
a)
+
Nu-(H)
N
N
N
N
INTRODUCTION
R
R
Ar
Ar
Nu
1
2
Considerable attention has been devoted to oxidative
cross-coupling reactions, also called cross-dehydrogena-
tive coupling (CDC), which generate a new C-C or C-het-
eroatom bond from C-H and C-heteroatom bonds, respec-
tively.1 Among the multitude of reactions developed in re-
cent years, especially the use of N-aryltetrahydroisoquino-
lines (1, N-aryl THIQs) or N,N-dimethylanilines (2) as sub-
strates in coupling reactions with nucleophiles have in-
spired many research groups (Scheme 1a).2 Since the first
reports by Miura and Murahashi using Fe- and Ru-cata-
lysts,3 an increasing number of catalysts, oxidants and nu-
cleophiles has been discovered for this type of reaction.4,5
Most inspiring have been the reports by the group of Chao-
Jun Li which used the combination of CuBr as catalyst to-
gether with tert-butyl hydroperoxide (tBuOOH) in decane
as oxidant to couple 1 with a large variety of compounds to
products of type 3 (Scheme 1b).6 A few dedicated mecha-
nistic investigations of this or closely related reactions have
been reported, including a computational study.7 How-
5 mol% CuBr
b)
+
Nu-H
N
N
1.0-1.3
(5.5
or
tBuOOH
M in decane)
equiv.
Ar
Ar
Nu
1
r.t.
to 100°C
up
3
Scheme 1. a) Oxidative Coupling Reactions with
Amines. b) Coupling of N-Aryl Tetrahydroisoquino-
lines with Nucleophiles using CuBr as Catalyst and
tert-Butyl Hydroperoxide as Oxidant
It is generally assumed that CuBr, as well as several other
transition metal salts and also iodide, act as catalysts to de-
compose tert-butylhydroperoxide into tert-butoxyl
(tBuO•) and tert-butylperoxyl radicals (tBuOO•) (Scheme
2).7b,7c,8 The nowadays common way of depicting this reac-
tion is based on proposals from Kharasch, Kochi and
Minisci.8a,8b,9,10 Kochi suggested the formation of a copper
peroxide complex 4 but could not rule out the involvement
of free tBuOO•.9b Based on measurements of very fast hy-
drogen atom transfer (HAT) rates for reactions between
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alkoxyl radicals and tBuOOH,11 Minisci suggested that
took as explanation for the observed formation of 6 in
tBuO• formed by reaction of tBuOOH and Cu(I) rapidly
generates tBuOO• in the presence of tBuOOH.8b The
mechanism depicted in Scheme 2 thus illustrates the com-
mon assumption that the key intermediate in such reac-
tions with tBuOOH is tBuOO•.
larger amounts than any product 3 in the early stages of the
reaction, regardless of the nucleophile’s reactivity.7b The
iminium ion 5a would then be formed by reversible heter-
olytic C-O bond cleavage, assisted by the Lewis-acidic cat-
alyst. Under reaction conditions, the equilibrium favors 6
and 5a could not be detected by NMR, unless acid was
added.
u
tB
H
OO
u
u
u
tB
H
OO
tB
tB
tB
O
OO
+
u
H
O
9
Ratnikov and Doyle later proposed a different mecha-
nism for such reactions.7c They had investigated a Rh-cat-
alyzed oxidative coupling reaction with N,N-dimethylani-
lines (2) in methanol, using aqueous tBuOOH as oxidant,
but also explored the use of CuBr and other metal catalysts.
They suggested that the initial reaction between 2 and
tBuOO• would be electron transfer (ET), furnishing the
ammoniumyl radical cation 8 and tert-butylperoxylate
(Scheme 3c). The latter would abstract a proton from the
acidified α-CH2 bonds, resulting in carbon radical 9, which
would then generate the iminium ion 5b by another ET to
a second tBuOO•. The observed peroxide 10 would thus
form by nucleophilic attack on the iminium ion, in compe-
tition with other nucleophiles present, including the sol-
vent.
uI r
B
uII r
B
H
O
( )
C
C
10
11
12
13
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uII r
B
u
tB
OO
)
C
(
4
+
u
u
OO
H
2O
tB
tB
H
OO
Scheme 2. CuBr-catalyzed Generation of Oxyl and Per-
oxyl Radicals from tert-Butylhydroperoxide
Oxidative coupling reactions of tertiary amines in gen-
eral are supposed to proceed via electrophilic iminium ions
5 (Scheme 3a). With N-aryl THIQs, these have been char-
acterized for reactions using DDQ as oxidant and CuCl2 as
catalyst together with oxygen, respectively.12 Substrate
studies led to the conclusion that the role of catalyst and
oxidant is chiefly to form the electrophile, and the nucleo-
phile scope is thus limited to those of sufficient reactivity
to attack the iminium ion.7b
The key difference to our proposal, ET instead of HAT,
was mainly rationalized by several kinetic isotope effect ex-
periments and by a significant decrease in rate upon intro-
ducing electron-withdrawing substituents into the arene
ring.7c A slope of −0.76 in a Hammett plot versus σ+ indi-
cated the development of a positive charge.13 While these
conclusions by Ratnikov and Doyle were convincing, they
had studied a somewhat different system. We therefore felt
challenged to find out whether our proposal was right or
wrong by distinguishing between the possible pathways via
HAT and ET, respectively.
a)
+
Nu-H
oxidation
+
N
N
N
-
H
R
R
R
5
Nu
Klussmann et al. tBuOOH in decane)
b)
(
t
t
Bu(O)O
Ar
Bu(O)OH
or
tBuOO
4
N
N
N
HAT
Ar
Ar
1
7
6
OOtBu
[CuBr]
N
RESULTS AND DISCUSSION
Ar
5a
tBuOO
et al.
t
BuOOH
in H
MeOH)
We decided to study exclusively the oxidation of amines
1 in the absence of nucleophiles to avoid complications in
the kinetics and analysis, and thus investigated the for-
mation of peroxide 6 (Scheme 4).
2O,
N
c) Doyle
(
tBuOO
tBuOOH
tBuOO
5b
N
N
N
Ar
Ar
Ar
Ar
tBuOO
ET
ET
tBuOO
2
9
mo
u r
C B
5
l
%
8
N
N
.
.
e u v
u
3 0 q i tB OOH
6
.
n
ecane
d
u
tB OO
5 5 M i
1
10
(
)
. .
,
r
t
R
R
tBuOO
N
D E
C
Ar
=
=
=
=
=
=
=
=
a:
c:
e:
:
e
R
M
R
H3
R
F
N
g R
F
S
N
O2
O
C
C
4
3
5
Scheme 3. a) Supposed General Mechanism for Oxida-
tive Coupling Reactions with Amines. b), c) Suggested
Oxidative Pathways in the Formation of Iminium Ions
from Amines
:
e
M
:
r
B
:
:
b R
d R
f R
h R
Scheme 4. Oxidation of N-Aryl Tetrahydroisoquino-
lines 1 to the Peroxides 6
The chosen reaction conditions differ from those origi-
nally employed by the Li group6 by a higher loading of the
oxidant tBuOOH (3.0 equiv.) and by the addition of dichlo-
roethane (DCE) as solvent. The former guaranteed full
conversion of 1 to the product 6, which is not necessary in
reactions with an added nucleophile that substitutes the
peroxide residue and thus regenerates the trapped oxidant.
The addition of DCE – in contrast to the “neat” reaction
conditions used by Li et al. which only contain decane from
the peroxide solution – resulted in cleaner reactions. This
Regarding the question of how the iminium ion interme-
diate is formed, we had previously suggested the formation
of the observable peroxide intermediate 6 as direct precur-
sor of iminium ion 5a (Scheme 3b).7b HAT from N-aryl
THIQ 1 to tBuO• or tBuOO• would produce the stabilized
carbon radical 7. Peroxide 6 would then be formed by rad-
ical recombination with tBuOO• or by peroxyl transfer
from a complex like 4. This radical pathway would thus
proceed without competition by nucleophiles, which we
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allowed us to conduct them in an NMR tube in deuterated
is not sufficient to clearly differentiate between ET and
DCE and to follow their progress directly by 1H-NMR with-
out any workup.
HAT. ρ-Values varying between −0.6 and −4.0 (versus σ or
σ+) have been measured for oxidation reactions of amines
that were suggested to proceed via ET,16,19 including the
aforementioned study by Ratnikov and Doyle which re-
ported ρ = −0.76 as determined from competition experi-
ments with substituted N,N-dimethylanilines 2.7c,13 Accord-
ingly, we subjected the amines 1a-1h to a reaction that has
been shown to proceed via HAT and not ET, to have a more
fitting comparison for the ρ value.
One would expect the oxidation of 1 via HAT to tBuOO•
and subsequent formation of 6 (Scheme 3b) to only show a
rather small rate dependency on electronic effects. In con-
trast, a pathway via single or twofold ET from the nitrogen
atom to tBuOO• (Scheme 3c) would be expected to show a
strong reduction in rate with increasingly electron-with-
drawing substituents. We therefore conducted a Hammett
plot analysis with amines 1 substituted in the para-position
of the N-aryl ring, by performing competition experiments
between different amine couples. This ensures direct ac-
cess to the relative rates of the reaction between radicals
and amines, while the rates of separate experiments for
each amine might be controlled by the activation of
tBuOOH by CuBr only. Separate experiments were also
deemed unsuitable in view of the difficulty to ensure equal
catalyst concentrations in each experiment, given the very
low solubility of CuBr in decane and DCE. Instead of meas-
uring initial rates or conversions at a given time, we moni-
tored the progress of the reaction by in situ 1H-NMR. The
relative rates k were then calculated from these datasets by
the ratio of logarithmic fractional conversions,14 also called
the Ingold-Shaw expression (see the Supporting Infor-
mation).15 The Hammett plot of log(k) versus σ+ shows a
good linear fit with a slope of ρ = −0.41 (Figure 1).
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Thus, we carried out a detailed time-resolved kinetic
study employing the laser flash photolysis (LFP) technique
on the reactions of N-aryl THIQs 1 with the cumyloxyl rad-
ical (PhC(CH3)2O•, CumO•), a genuine HAT reagent
(Scheme 5).20
nm
355
Ph
O
Ph
O
LFP
Ph
+
O
N
N
O2 CH CN
,
3
1
7
R
R
a
:
c
:
=
=
:
:
=
=
:
f
=
R
CN
d
e
R
R
R
R
Br
CF3
OMe
H3
: =
g R
SF5
Scheme 5. HAT Reactions from Amines 1a-g to the
Cumyloxyl Radical Generated by Laser Flash Photoly-
sis of Dicumyl Peroxide in MeCN
CumO• and tBuO• are known to display almost identical
HAT reactivities,21 and both radicals undergo HAT from
the α-C−H bonds of tertiary amines with second-order rate
constants (kH) that, in aprotic solvents, exceed 108 M-1 s-
1 21d,22
.
While tBuO• is characterized by a weak absorption
band in the UV region of the spectrum (λmax = 280 nm),23
CumO• displays an absorption band in the visible region
(λmax = 485 nm in aprotic solvents),24 a feature that makes
the direct study of its reactions particularly convenient,
employing time-resolved techniques such as LFP. Most im-
portantly, both radicals are relatively weak one-electron
oxidants (in MeCN, E0
= -0.30 and -0.19 V/SCE, for
•
−
RO /RO
tBuO• and CumO•, respectively), and are known to un-
dergo ET reactions only with substrates characterized by
very low oxidation potentials such as polyalkylated ferro-
cenes.25
Figure 1. Hammett plot analysis of the formation of substi-
tuted peroxides 6, log k refers to relative rate constants from
competition experiments.
A similarly good linear fit was obtained when the rate
data was plotted against Hammett’s σ parameters and
against the reduction potential of amines 1a-1h as deter-
mined by cyclic voltammetry, respectively (see the Sup-
porting Information, Figures S2-S3). A correlation with the
reduction potential could be regarded as a strong indica-
tion for ET being the rate-controlling step;16 however, HAT
processes also have a polar character and the same corre-
lation has been observed in this case as well.17 For reasons
of consistency, a correlation with σ+ values will be used
throughout the manuscript.
CumO• was generated by 355 nm LFP of 0.8-1.0 M di-
cumyl peroxide solutions in MeCN, 2,2,4-trimethylpentane
(isooctane), 1,2-dichloroethane (DCE) and 2-methyl-2-bu-
tanol (MBOH), respectively. In argon-saturated solution,
the strong absorption of carbon radical 7 formed following
HAT prevented the determination of the rate constants. As
an example, the time-resolved absorption spectra for reac-
tion of CumO• with 1a, 1c and 1f (R = OMe, H and CN, re-
spectively), measured in argon-saturated MeCN solution,
are displayed in the Supporting Information (see Figures
S57-S59). Accordingly, all the kinetic experiments were
carried out in oxygen-saturated solution, where carbon
radical 7 is scavenged by fast reaction with O2.26
While the observed ρ-value is in full agreement with pre-
vious measurements of HAT from C-H bonds to tBuO•,18 it
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The second-order rate constants (kH) for HAT from 1a-
1g to CumO• were obtained from the slope of the observed
rate constant (kobs) vs [substrate] plots, the kobs values were
measured by following the decay of the CumO• visible ab-
sorption band at the different substrate concentrations
employed. The strong absorption of 1h (R = NO2) at the
laser excitation wavelength prevented a kinetic study with
this substrate.
9
All the kobs vs [substrate] plots thus obtained are dis-
played in the Supporting Information (Figures S60-S71).
The corresponding kH values in different solvents are col-
lected in Table 1. Also included in this table are the kH val-
ues measured for reaction of CumO• with 1c-D2, the deriv-
ative of 1c bearing two deuterium atoms in the benzylic α-
position of the amine, and those measured previously for
reaction of CumO• with tBuOOH in different solvents.11b
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Figure 2. Hammett plot analysis of HAT reactions from
amines 1a-g to the cumyloxyl radical generated by laser flash
photolysis in MeCN.
TABLE 1. Second-Order Rate Constants (kH) for HAT
from N-Aryl THIQs 1a and tBuOOHb to the Cumyloxyl
Radical (CumO•) Measured in Different Solvents.
The ρ value for this HAT reaction, −0.31, is clearly similar
to the one obtained from the plot displayed in Figure 1,
strongly supporting the hypothesis that the key step of
these reactions is HAT to an oxyl radical and not ET.
Entry
Substrate
Solvent
kHAT (M-1s-1)
Interestingly, the rate constants for HAT from N-aryl
THIQs 1a-g to cumyloxyl measured in acetonitrile were
generally higher than the above-mentioned values meas-
ured for the corresponding tBuOOH (Table 1). The rate
constant for HAT from 1c to CumO•, for example, was de-
termined as kH = 2.8∙108 M-1s-1 in acetonitrile (entry 4),
while for HAT from tBuOOH a value kH = 8.7∙106 M-1s-1 (en-
try 15) has been reported.11b The solvent effect found for N-
aryl THIQs 1 was relatively small with the rate constants
generally decreasing with increasing solvent polarity (com-
pare entries 2, 4, 6, 7 and 10, 11), in line with previous inves-
tigations.21e,28 In contrast, the solvent effect for HAT from
tBuOOH has been reported as “dramatic” (entries 13-16).11b
When the values for the N-aryl THIQs are compared with
those reported for tBuOOH (entries 1-12 vs. 13-16), it is ob-
vious that the amines generally react faster or at least with
similar rates. We thus conclude that the common assump-
tion outlined in Scheme 2 that the reactions following cat-
alytic decomposition of tBuOOH into radicals are gener-
ally driven by peroxyl radicals is not correct. At least in the
present case of reactions involving N-aryl THIQs 1, tBuO•,
which, as mentioned above, exhibits almost the same HAT
reactivity as CumO•,21 will predominantly react by HAT
from the amines and not from tBuOOH.
1
1a (OMe)
1c (H)
CH3CN
isooctane
isooctane
CH3CN
CH3CN
MBOHc
DCE
4.8±0.10∙108
5.2±0.1∙108
2.19±0.04∙108
2.80±0.02∙108
1.57±0.02∙108
1.98±0.06∙108
1.61±0.08∙108
2.17±0.07∙108
2.01±0.02∙108
1.53±0.02∙108
9.58±0.02∙107
1.65±0.02∙108
2.5∙108
2
3
1c-D2 (H)
1c (H)
4
5
1c-D2 (H)
1c (H)
6
7
1c (H)
8
1d (Br)
CH3CN
CH3CN
CH3CN
DCE
9
1e (CF3)
1f (CN)
1f (CN)
1g (SF5)
tBuOOH
tBuOOH
tBuOOH
tBuOOH
10
11
12
13b
14b
15b
16b
CH3CN
CCl4
benzene
CH3CN
tBuOH
1.3∙108
8.7∙106
6.7∙106
aThis work. Measured in oxygen-saturated solution at T =
25°C by following 355 nm LFP of 0.8-1.0 M dicumyl peroxide
solutions. The kH values were obtained from the slope of the
kobs vs [substrate] plots, while the kobs values were measured
by following the decay of the CumO• visible absorption band
at 490 nm. bRef. 11b. cMBOH: 2-methyl-2-butanol.
For comparison, we computed corresponding Hammett
plots at the UM06-2X/6-311+G(2df,2pd)//UM06-2X/6-
31+G(d,p) level of DFT (Figure 3). We studied various reac-
tion pathways of the substituted amines 1, but only address
the abstractions with tBuO• and tBuOO• here.
The data displayed in Table 1 show that in the reactions
of CumO• with N-aryl THIQs 1a-1g the kH values decrease
with decreasing electron donating ability of the N-aryl sub-
stituent, in line with the electrophilic character of the ab-
stracting radical.27 The Hammett plot for HAT from 1a-1g
to CumO• is displayed in Figure 2.
The best agreement with the experimental Hammett
data was achieved with a HAT reaction from amines 1 to
tBuO•, giving a ρ value of −0.43 against σ+ (Figure 3a, c.f.
Figure 1). In contrast, HAT to tBuOO• produced a much
higher ρ value of −0.92 against σ+ (Figure 3b). The greater
sensitivity in the hydrogen abstraction with tBuOO• is in-
dicative of its later transition state as compared with
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tBuO•.16 For comparison, a Hammett plot was constructed
1c-D2 (KIE type 1), a competition experiment with 1c and
using CumO• as the hydrogen abstraction agent for cali-
bration of the method. The resulting sensitivity agreed rea-
sonably well with the experimental value (Figure 3c, c.f.
Figure 2).
1c-D2 (type 2), and an intramolecular competition experi-
ment with 1c-D (type 3) (Scheme 6). Only the experiment
of type 1 can truly reveal whether C-H bond cleavage is in-
volved in the rate-controlling step, while types 2 and 3
might only reflect the relative rates of later steps - infor-
mation that is nevertheless potentially very useful.29 As be-
1
fore, we monitored the reaction progress by H-NMR and
9
calculated the kinetic isotope effect of the type 2 experi-
ments by the ratio of logarithmic fractional conversions
(see the Supporting Information).14
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32
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42
43
44
45
46
47
48
49
50
51
52
53
54
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=
KIE
1:
intermolecular,
/kD 2.1)
separate
experiment type
(kH
5 mol% CuBr
tBuOOH
N
N
3.0
equiv.
Ph
Ph
M in decane)
(5.5
1c
H
D
H
tBuOO H
6c
r.t.
DCE,
5 mol% CuBr
tBuOOH
N
N
3.0
equiv.
Ph
Ph
M in decane)
(5.5
1c-D2
D
tBuOO D
6c-D
r.t.
DCE,
=
KIE
KIE
2:
intermolecular
/kD 5.3)
experiment type
competition experiment
(kH
5 mol% CuBr
tBuOOH
+
1c 1c-D2
+
6c 6c-D
3.0
equiv.
each)
equiv.
(0.5
M in decane)
(5.5
r.t.
DCE,
=
3:
intramolecular
/kD 5.3)
experiment type
(kH
5 mol% CuBr
tBuOOH
N
N
3.0
equiv.
Ph
Ph
M in decane)
(5.5
1c-D
H
D
tBuOO
H/D
6c 6c-D
r.t.
DCE,
/
Scheme 6. Kinetic Isotope Effects in the Formation of
6
The values thus obtained were 2.1 ± 0.13, 5.3 ± 0.38 and
5.3 for KIEs of types 1, 2 and 3, respectively. The primary
kinetic isotope effect of type 1 clearly indicates that C-H
bond cleavage is involved in the rate-controlling step.
Ratnikov and Doyle had measured KIEs of type 2 and 3
for N,N-dimethylaniline and obtained values of 1.71 and
2.46, respectively.7c These significantly smaller values indi-
cate that C-H bond cleavage has a stronger influence on
the rate in our system than in Doyle’s, supporting HAT and
ET as rate controlling steps, respectively. In a previous
study with 1c, using CuCl2 and oxygen as terminal oxidant,
we had determined a value of 1.3 for a type 1 experiment,
suggesting a secondary KIE due to ET to Cu(II).30 This
lower value, compared with the one obtained here, also
supports the suggested mechanisms.
Figure 3. Computational Hammett plot analysis of HAT reac-
tions from amines 1 to the a) tert-butoxyl radical, b) tert-bu-
tylperoxyl radical and c) cumyloxyl radical. Also shown are key
distances (Å) in the HAT transition states.
Determining the KIE of type 1 in the laser-flash-photoly-
sis-initiated reaction of Scheme 5 between 1c and the
cumyloxyl-radical gave values of 1.78 and 2.37 in acetoni-
trile and isooctane, respectively (Table 1, entries 2-5). In ad-
ditional DFT calculations at the UM06-2X/6-31G+G(d,p)
level, we obtained KIE values of 2.7, 2.7 and 4.7 for the re-
actions between 1 and tBuO•, CumO• and tBuOO•, respec-
tively. The KIE measured in the type 1 experiment (2.1,
Scheme 6) is much closer to the value computed for tBuO•
The results obtained from this experimental and compu-
tational study (Figures 1-3) provide strong support to the
hypothesis that the reaction of Scheme 4 proceeds pre-
dominantly by HAT from amines 1 to tBuO•, rather than to
tBuOO•.
For additional experimental information, we also em-
ployed the parent amine 1c in kinetic isotope effect (KIE)
experiments, performing separate experiments with 1c and
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(2.7) than for tBuOO• (4.7). The results from these KIE
Using 6.0 equivalents of tBuOOH, a very high KIE value
studies support the notion that the formation of 6 proceeds
via rate-controlling HAT and involves predominantly
tBuO•.
of 8.3 was measured (entry 1), compared with the value of
5.3 as determined before under standard conditions (entry
2). Performing the reaction in acetonitrile resulted in a
lower KIE with a value of 4.3 (entry 3). Using only one
equivalent of tBuOOH in the standard reaction was not
possible, since the formation of 6 requires the use of two
equivalents, one as an oxidant and one as a coupling part-
ner. Therefore, we performed the reaction with one equiv-
alent of tBuOOH as oxidant in the presence of one equiva-
lent of dimethylmalonate (11) as nucleophile to give prod-
uct 12. Under these conditions, a KIE value of 3.0 was de-
termined (entry 4).
In a previous study using Li’s original conditions for the
oxidative coupling of 1c with dimethylmalonate, we had
found a KIE value of 3.4 for a type 3 experiment.7b In Ru-
catalyzed reactions of N,N-dimethylaniline using tBuOOH
as oxidant, KIE experiments of type 3 had also resulted in
lower values of 2.2 and 3.5, respectively.7a,31
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We thus wondered whether an interconnected system of
HAT reactions plays a role, leading to different and rela-
tively high values in type 2 and 3 experiments and making
these susceptible to reaction conditions. For tBuO•,
formed by Cu-catalysis, there is a competition between the
HAT reaction with tBuOOH (HAT1) and with 1 (HAT2),
which is influenced by the individual rate constants kHAT1
and kHAT2, respectively, and the concentrations [tBuOOH]
and [1c] (Scheme 7).
These results are in line with the model of Scheme 7. An
increased concentration of tBuOOH increases the rate of
HAT1, thus increasing the relative importance of HAT3
over HAT2 and thereby the overall KIE. In acetonitrile,
HAT1 becomes much slower compared with less polar sol-
vents (Table 1, entries 13-14 versus 15), while HAT2 rather
increases (Table 1, entry 7 versus 4). Under these condi-
tions, HAT2 will become more favoured than HAT3, result-
ing in a lower KIE. Finally, by using only one equivalent of
tBuOOH, HAT1 will be slowed down compared with stand-
ard conditions, which again decreases the KIE.
1c
N
Ph
tBuOH
[Cu]
t
t
tBuO
BuOOH
BuOOH
lower KIE
2.7)
(DFT:
kHAT2
t
BuOOH
tBuOH
[Cu]
kHAT1
The HAT sequence hypothesized in Scheme 7 was ex-
plored with DFT (Figure 4). HAT2 has a computed barrier
of 9.6 kcal⋅mol-1, via transition state 1c-tBuO-TS that is 0.8
kcal⋅mol-1 lower in energy than that for HAT1 in DCE. The
preference switches in the gas phase (−1.2 kcal⋅mol-1). HAT3
has a significantly higher barrier of 19.1 kcal⋅mol-1 via tran-
sition state 1c-tBuOO-TS. The general trends drawn from
the computed profile are indeed consistent with the KIE
data from Table 2 and with the solvent effects seen in Table
1.
N
Ph
kHAT3
KIE
4.7)
higher
(DFT:
7c
tBuOO
t
BuOOH
1c
Scheme 7. HAT Sequence Affecting the KIE
As indicated in Scheme 7, our DFT calculations predict a
significantly lower KIE for HAT2 than for HAT3, the reac-
tion of tBuOO• with 1c. We thus probed this prediction by
changing the reaction conditions in KIE experiments of
type 3, in order to vary the relative importance of pathways
HAT1 versus HAT2. This would in turn affect the relation
of HAT2 versus HAT3 in the formation of radical 7c as pre-
cursor to the observed product 6c (Table 2).
Table 2. Kinetic Isotope Effect Experiments of Type 3
Using Different Reaction Conditions.a
5 mol% CuBr
Me
Me
CO2
t
BuOOH
+
or
1c-D
r.t.
N
N
solvent,
CO2
Ph
Ph
tBuOO
MeO2C
12 12-D
H/D
H/D
11
Me
CO2
6c 6c-D
/
/
Entry Equiv.
11
Equiv.
tBuOOH
Solvent Prod- KIEb
uct
1
0
6.0
3.0
3.0
1.0
DCE
DCE
CH3CN
DCE
b
6c
6c
6c
13
8.3
5.3
4.3
3.0
2
3
4
0
Figure 4. Gibbs free energy profile (kcal/mol) for the
competition between tBuO• and tBuOO•. Values at the sta-
tionary points taken from DFT calculations in solution [gas
phase]. Black: HAT1 followed by HAT3; blue: HAT2.
0
1.0
aUsing 5.5 M tBuOOH in decane. Ratio 6c-D/6c and 12-
D/12, respectively, by 1H-NMR.
The feasibility of an ET mechanism was evaluated by
computing the reaction Gibbs free energies in solution for
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the electron transfer from 1 to tBuO• and tBuOO• (Scheme
charge and spin density analysis (Figure 5). Overall, the
computed results suggest a direct HAT process.
8). For the solvent used in this reaction, DCE, the com-
puted Gibbs free energies are significantly higher than
those for the corresponding HAT processes shown in Fig-
ure 4. To explore the limiting case of a very polar solvent,
the Gibbs energies were also computed in a high dielectric
(H2O) where the ions are anticipated to be fully solvated
and separated. The resulting values remain significantly
higher than those for the related HAT processes. The large
computed reaction free energies indicate that an ET pro-
cess with substrate 1 using either tBuO• or tBuOO• as elec-
tron acceptor is unlikely under the reaction conditions.
In light of these results, we wondered about the differ-
ences and similarities in the mechanistic proposal put for-
ward by Ratnikov and Doyle. If ET and not HAT is indeed
the key step of substrate activation in their system, it must
be due to the difference in substrates and reaction condi-
tions – N,N-dimethylanilines versus N-aryl THIQs, Rh- ver-
sus Cu-catalysis, methanol/water versus DCE/decane. This
would not be unlikely, as it has been reported that a caro-
tene reacts with tBuOO• by ET34 and that polar protic sol-
vents facilitate ET reactions to peroxyl radicals.35
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60
∆
GDCE=33.1
ET
In order to assess this effect, we attempted to study N,N-
dimethylanilines as substrates and dirhodium caprolac-
tamate as catalyst, respectively, under otherwise identical
reaction conditions as shown in Scheme 4. However, the
anilines gave too many byproducts, which prevented ob-
taining a reliable Hammett plot. Substituting CuBr by the
rhodium catalyst resulted in rates too high to study the
competition between the different amines 1; even 1h gave
complete conversion after only five minutes. In any case,
Ratnikov and Doyle obtained identical KIE’s with Cu, Fe,
Co, Ru and Rh-catalysts and thus suggested that these ac-
tivate tBuOOH in the same manner without significant in-
volvement in the rest of the reaction.7c We did manage to
obtain a Hammett plot for the reaction of some N-aryl
THIQs 1 under the conditions used by Ratnikov and Doyle
(Figure 6). Not all of the substituted amines 1 could be used
for reasons of solubility and because some of the different
products formed could not be distinguished in the 1H-NMR
spectra – next to the peroxides 6, hemiaminal ethers 14
were also formed from methanol.7c Although the linear fit
is not as good as in the Hammett plots shown above, the
trend is very clear.
+
+
tBuO
Ph
tBuO
N
N
∆
GH O=24.1
2
Ph
1c
1c
1c-ox
1c-ox
∆
=47.9
GDCE
ET
+
+
tBuOO
Ph
tBuOO
N
N
∆
GH O
=38.6
2
Ph
Scheme 8. Computed Reaction Free Energies in Solu-
tion for SET at the UM06-2X(CPCM)/6-
311+G(2df,2pd)//UM06-2X/6-31+G(d,p) Level
Alternatively, the ET and proton transfer could be pro-
posed as taking place in the same elementary step in a for-
mal proton-coupled electron transfer (PCET) process.32 If
PCET was operative, significant spin density would be ex-
pected to accumulate on the nitrogen atom during an elec-
tron transfer from the substrate and the transferring hy-
drogen would exhibit a large partial positive charge.33 In 1c-
tBuO-TS, the majority of the spin density is localized on
the oxygen atom (69%) while only 9% is localized on the
nitrogen atom (Figure 5). Furthermore, the NBO partial
charge on the transferring hydrogen is only +0.29, which is
not much larger than the charge on the axial hydrogen
(+0.24) of the other amine methylene group. In compari-
son, 1c-tBuOO-TS exhibits a slightly greater spin density
on the nitrogen (12%) and a charge on the transferring hy-
drogen (+0.35) that is still less than expected for a proton
transfer.
Figure 5. Geometries for transition states 1c-tBuO-TS and 1c-
tBuOO-TS. Displayed are Mulliken spin densities percentages
in blue, NBO partial charges in red, and bond distances (Å) in
black.
Figure 6. Hammett plot analysis of the oxidation of 1 in
MeOH using Rh2(cap)4 and aqueous tBuOOH.
With ρ = −0.16, the slope has become even shallower
than before (ρ = −0.41) and is thus consistent with a HAT
reaction and not with ET. It differs strongly from the one
reported for N,N-dimethylanilines under these conditions
(ρ = −0.76).7c,13 The reduced slope could be due to the
Taken together, a stepwise ET/proton transfer mecha-
nism is unlikely on account of the prohibitive computed
Gibbs energies for the ET (Scheme 8). Alternatively, a
PCET mechanism is also unlikely as determined from
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strong reduction of kHAT1 in polar protic medium (Table 1,
entries 13-16), which disfavors involvement of tBuOO• in
the HAT reaction from 1.
tBuO• and tBuOO• can be hydrogen atom acceptors in re-
actions with amines 1, forming radical 7 (HAT2 and HAT3,
respectively, Scheme 9b). This reacts further to peroxide 6,
which decomposes to the iminium intermediate 5 by
Lewis-acid catalysis, leading to the coupling products 3 af-
ter attack from various nucleophiles.
In order to assess the remaining difference, the structure
of the amine substrates, we subjected some p-substituted
N,N-dimethylanilines to the time-resolved kinetic study in
acetonitrile as shown in Scheme 5 above. The pertinent kobs
versus [substrate] plots for reactions with CumO• are dis-
played in the Supporting Information (Figures S72-S78).
The second order rate constants thus obtained were rather
similar to those obtained with the N-aryl-THIQs and simi-
lar kinetic solvent effects were observed for the two series
of substrates (see Table S7). The Hammett plot analysis
gave a slope of ρ = −0.53 (see Figure S79). The Hammett
plots constructed by DFT calculations gave ρ = −0.90 for
HAT from the anilines to tBuO• and ρ = −1.25 for HAT to
tBuOO• (see the Supporting Information for details of the
kinetic and computational studies). Support for HAT in-
stead of ET was also provided by a previous study of the
reaction between N,N-dimethylanilines and CumOO•.36
Furthermore, the reduction potentials for 1a-h and simi-
larly substituted anilines lie in the same range (see the Sup-
porting Information and compare with reported values16a).
In contrast to what is often proposed in this and related
reactions, tBuO• was found to be the dominant acceptor
radical in the reaction with 1, in line with the finding that
the rate constant of HAT2 is generally larger or at least sim-
ilar to the rate constant of HAT1. Also, HAT2 is decreased
less by solvent polarity than HAT1. Accordingly, the rela-
tive contribution of HAT2 and HAT3 to the formation of
the amine-peroxide products 6 is susceptible to the exact
reaction conditions. This could be qualitatively demon-
strated by changes in intramolecular kinetic isotope ef-
fects, which ranged from 3 to 8, depending on the concen-
tration of tBuOOH or the solvent.
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The previous proposal by Ratnikov and Doyle of an elec-
tron transfer pathway in the formation of peroxide prod-
ucts from N-aryl amines is not supported by this study. In-
stead, our results indicate that also in the highly polar re-
action medium used in their study – a mixture of methanol
and water – substrate 1 is activated by HAT. However, a
different mechanism in their reaction of study cannot be
ruled out as they used a different catalyst and different
amines (N,N-dimethylanilines).
These results suggest the possibility that the reactions
studied by Ratnikov and Doyle actually proceed by HAT as
well. However, ET cannot be ruled out with certainty.
The experimental results obtained in this study cannot
clearly explain the formation of the observed product 6
from the putative radical 7 (Scheme 9b). However, the pre-
viously suggested7b radical combination appears reasona-
ble. In a first instance, the copper-catalyzed decomposition
of tBuOOH produces tBuO• and tBuOO• at the same rate.
The majority of tBuO• reacts via HAT2, forming the major-
ity of C-radical 7, thus leading to a relatively high concen-
tration of unreacted tBuOO•. It has been reported that di-
merization or other self-decomposition pathways of ter-
tiary peroxyl radicals are slow while their reaction with car-
bon radicals is fast.37 Accordingly, it appears reasonable
that under these conditions, the amino-peroxides 6 are
formed by radical combination in high yields. It has also
been suggested8c that such reactions with tBuOO• fulfill
the criteria of the persistent radical effect.38 Nevertheless,
these are reactive species and our attempts to observe
them in the present reaction by EPR spectroscopy have
been in vain. Whether the bond-forming event that pro-
duces peroxide 6 is preceded by ET, as suggested before,7c
remains questionable – at least in the nonpolar medium
employed here which would disfavor the creation of
charge-separated species.
SUMMARY AND CONCLUSIONS
In summary, the results from the present experimental
and computational study clearly indicate that the oxidative
coupling of N-aryl tetrahydroisoquinolines
1
with
tBuOOH, catalyzed by CuBr, proceeds via hydrogen atom
transfer (HAT) from the amines to directly give an inter-
mediate carbon centered radical 7 (Scheme 9).
a)
t
BuOOH
+
t
tBuO
tBuOO
tBuOH
BuOOH
HAT1
IBr
CuII
Cu
Br(OH)
+
H
2O tBuOO
t
BuOOH
b)
tBuO
tBuOH
HAT2
HAT3
tBuOH
tBuOO
N
N
N
Ar
Ar
Ar
Ar
1
7
6
tBu
OO
tBuOO
[CuBr]
Nu-H
-
t
BuOOH
N
N
Ar
3
5
tBuOO
Nu
The presence of nucleophiles, required to synthesize
coupling products 3 and usually present in all synthetic
studies, should in principle not affect the mechanisms dis-
cussed in the present study. Studies monitoring the reac-
tion progress indicate this to be the case for various nucle-
ophiles.7b Nucleophiles that can be involved in fast HAT
Scheme 9. Mechanistic Proposal for the Oxidative
Coupling of Amines 1 with tBuOOH
The role of CuBr is to catalyze the decomposition of the
oxidant tBuOOH into tBuO• and tBuOO• (Scheme 9a). An
additional source of tBuOO• is the fast hydrogen atom
transfer reaction from tBuOOH to tBuO• (HAT1). Both
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(3) a) Murata, S.; Miura, M.; Nomura, M. Chem. Commun. 1989,
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ucts. The reported reaction between 1c and 2-naphthol,
which led to the formation of significant amounts of
binaphthol, could be such a case.6f
Apart from clarifying mechanistic details of a reaction
that inspired researchers world-wide, the present study
also illustrates some issues that could be relevant for all
other oxidative coupling reactions utilizing a similar com-
bination of redox-active catalyst and tBuOOH.39 The com-
mon assumption that oxidative coupling reactions with
tBuOOH are predominantly driven by tBuOO• should be
treated with caution. While its formation by HAT from
tBuOOH to tBuO• is fast, HAT reactions from the sub-
strates employed can be faster. Also, the interplay of HAT
reactions 1, 2 and 3 can significantly alter the results of ki-
netic isotope studies, an effect that should be considered
when comparing results obtained under different condi-
tions.
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ASSOCIATED CONTENT
Supporting Information. Experimental and computational
details including product characterization and kinetic experi-
ments. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
bietti@uniroma2.it
thiel@mpi-muelheim.mpg.de
klusi@mpi-muelheim.mpg.de
Present Addresses
§ Present address: Department of Chemistry, Indian Institute
of Technology Bombay, Powai, Mumbai 400076, India
ACKNOWLEDGMENT
Financial support from the DFG (Heisenberg scholarship to
M.K., KL 2221/4-1) and the MPI für Kohlenforschung is grate-
fully acknowledged. E.B. and M.K. thank the NMR department
for their generous support and Christian Wille and Nobuhito
Uemiya for CV measurements. M.S. and M.B. gratefully
acknowledge financial support from the Ministero
dell'Istruzione dell'Università e della Ricerca (MIUR), project
2010PFLRJR (PRIN 2010-2011), and thank Prof. Lorenzo Stella
for the use of a LFP equipment. The authors thank M. O. Rat-
nikov and M. P. Doyle for kindly sharing their data.
REFERENCES
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Graphic entry for the Table of Contents (TOC):
tBuO tBuOH
1
2
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HAT
HAT
N
N
N
Ar
tBuOO
Ar
Ar
Nu
tBuOH
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Scheme 1
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Scheme 2
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