Revisiting the Radical Initiation Mechanism of the Diamine-Promoted Transition-Metal-Free Cross-Coupling Reaction

Article abstract of DOI:10.1021/jacs.6b03442

Radical chain reactions leading to C-C bond formation are widely used in organic synthesis, and initiation of the radical chain process usually requires thermolabile radical initiators. Recent studies on transition-metal-free cross-coupling reactions between aryl halides and arenes have demonstrated an unprecedented initiation system for radical chain reactions, where the combination of simple organic additives and a base was used in place of conventional radical initiators. Among them, the combination of N,N′-dimethylethylenediamine (DMEDA) and t-BuOK is one of the most efficient and representative reaction systems, and the radical initiation mechanism of this system has attracted considerable research interest. In this study, through the combination of kinetic studies, deuterium labeling experiments, and DFT calculations, the radical initiation mechanism of the diamine-promoted cross-coupling reaction was carefully reinvestigated. In light of the present study, a mechanistic network of radical initiation in the DMEDA/t-BuOK system was revealed, which differs dramatically from the previously realized single radical initiation pathway. In this mechanism, the diamine acts as a hydrogen atom donor and plays a dual role as both "radical amplifier" and "radical regulator" to initiate the radical chain process as well as to control the concentration of reactive radical species. This represents a rare example of a structurally simple molecule playing such a subtle role in the radical chain reaction system. The present study sheds some light on the novel radical initiation mode in transition-metal-free cross-coupling reactions following a base-promoted homolytic aromatic substitution (BHAS) mechanism, and may also help to understand the mechanism of relevant reactions.

Full text of DOI:10.1021/jacs.6b03442

Article
pubs.acs.org/JACS
Revisiting the Radical Initiation Mechanism of the Diamine-
Promoted Transition-Metal-Free Cross-Coupling Reaction
Li Zhang, Huan Yang, and Lei Jiao*
Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100084, China
S Supporting Information
*
ABSTRACT: Radical chain reactions leading to C−C bond
formation are widely used in organic synthesis, and initiation of
the radical chain process usually requires thermolabile radical
initiators. Recent studies on transition-metal-free cross-coupling
reactions between aryl halides and arenes have demonstrated an
unprecedented initiation system for radical chain reactions,
where the combination of simple organic additives and a base
was used in place of conventional radical initiators. Among them,
the combination of N,N′-dimethylethylenediamine (DMEDA)
and t-BuOK is one of the most efficient and representative
reaction systems, and the radical initiation mechanism of this
system has attracted considerable research interest. In this study,
through the combination of kinetic studies, deuterium labeling experiments, and DFT calculations, the radical initiation
mechanism of the diamine-promoted cross-coupling reaction was carefully reinvestigated. In light of the present study, a
mechanistic network of radical initiation in the DMEDA/t-BuOK system was revealed, which differs dramatically from the
previously realized single radical initiation pathway. In this mechanism, the diamine acts as a hydrogen atom donor and plays a
dual role as both “radical amplifier” and “radical regulator” to initiate the radical chain process as well as to control the
concentration of reactive radical species. This represents a rare example of a structurally simple molecule playing such a subtle
role in the radical chain reaction system. The present study sheds some light on the novel radical initiation mode in transition-
metal-free cross-coupling reactions following a base-promoted homolytic aromatic substitution (BHAS) mechanism, and may
also help to understand the mechanism of relevant reactions.
1
2
INTRODUCTION
promoted homolytic aromatic substitution (BHAS) reaction,
include inter/intramolecular coupling between aryl halides and
■
Free-radical reactions constitute an important reaction category
7
−9
1
arenes to form biaryls, and Heck-type coupling between aryl
in organic chemistry. Among them, C−C bond formation
10
halides and olefins to form aryl-substituted alkenes, in which
formal C−H arylations are achieved. A wide variety of organic
through radical chain process has contributed greatly to the
2
toolbox for synthetic chemists. Radical initiation is a significant
7
b,c,m,s,w,8a,c,d,f,g,9e,10b,c
additives, such as 1,10-phenanthrolines,
process in radical chain reactions. For synthetic reactions
involving a radical chain process, thermal decomposition of
radical initiators is the most often used initiation method
7a,s,8d,g
7l,o,u,8a,e,10a
1
,2-diamines,
alcohols and 1,2-diols,
amino
7d,f
7n,p
acids,
hydrazine derivatives,
and N-heterocyclic carbe-
7h
1
−3
nes, have been proved effective promotors for these reactions.
Interestingly, although these organic additives (most of them are
thermostable molecules) are distinct from conventional radical
initiators, they initiate the radical chain process efficiently. The
development of these reactions not only brought about new
advances in cross-coupling methodology, but also enabled an
unprecedented initiation system for radical chain reactions.
The radical initiation mechanism of these reaction systems has
been a problem of interest in radical chemistry since their
discovery. To date, the cross-coupling (chain propagation)
compared with others (e.g., photolysis and radiation).
Organic molecules with thermolabile chemical bonds that
could undergo homolysis upon heating, such as peroxides (e.g.,
benzoyl peroxide, BPO) and azo compounds (e.g., 2,2′-
azoisobutyronitrile, AIBN), are usually employed as radical
initiators.
4
Since 2008, studies on transition-metal-free C−C cross-
5
coupling reactions have shown that radical chain reactions could
be initiated in a rather different way. Traditional cross-coupling
reactions employ transition metal complexes as catalysts to
promote the cross-coupling process through organometallic
12
mechanism has been made clear. It is generally accepted that
the generation of aryl radical from aryl halide and addition of the
aryl radical to arene are key steps for cross-coupling, and
6
mechanism. Recent studies have established a distinct approach,
in which coupling between aryl halides and arenes (or olefins) is
promoted by small molecule organic additives in the presence of
7
−11
base through radical chain mechanism (Scheme 1).
These
Received: April 4, 2016
transition-metal-free coupling reactions, classified as the base-
©
XXXX American Chemical Society
A
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subsequent deprotonation, single electron transfer (SET), and
CX bond cleavage sustain the chain process (Scheme 1b).
RESULTS AND DISCUSSION
■
The aim of this research is to elucidate the role of diamine in the
radical initiation process. An extensive literature survey showed
that, in transition-metal-free cross-coupling reactions, organic
additives were generally believed to function as electron
Scheme 1. Transition-Metal-Free Cross-Coupling Reaction
between Aryl Halides and Arenes (Ar = Aryl Group)
1
2c,d
7b,c,f,h,j,k,m,o,q,8a,c,d,f,g
donors,
donors.
ligands,
or precursors to electron
In the DMEDA/t-BuOK reaction system,
7
e,n,p,12e
possible initiation mechanisms include: (a) direct single electron
transfer from DMEDA to the aryl halide; (b) DMEDA acting as a
ligand to form alkali metal alkoxide complex, which then transfers
an electron to the aryl halide; (c) DMEDA being converted to an
electron-rich intermediate under the reaction conditions, which
then acts as an electron donor to initiate the reaction (Scheme 2).
Scheme 2. Possible Initiation Mechanisms of the DMEDA/t-
BuOK Reaction System
However, the chain initiation mechanism with various
“unconventional initiators” still remains elusive, and only limited
experimental efforts have been made to address this
1
0d,12e,f,h
issue.
A general mechanistic interpretation is that the
organic additive either directly functions as an electron donor or
generates an electron donor under the reaction conditions, which
then undergoes electron transfer to aryl halide to produce aryl
12
radical as the initiator radical (Scheme 1b), but the initiation
mechanism has not been revealed in sufficient detail. To
understand the nature of this novel radical initiation system
and to utilize it in designing new radical chain reactions for
synthesis, it is important to clearly identify the role of the organic
additives through in-depth mechanistic studies.
Among the reaction systems that could initiate the transition-
metal-free cross-coupling, the combination of N,N′-dimethyle-
thylenediamine (DMEDA) and t-BuOK is a most effective and
Murphy, Tuttle, and co-workers found that ethylene-
deuterated DMEDA derivatives exhibited no radical initiation
12e
activity. On this basis, they concluded that cleavage of the C−
H bond on the ethylene group played a critical role in the radical
initiation process. Therefore, initiation mechanisms 1 and 2 were
believed to be unreasonable, and initiation mechanism 3 was
proposed: DMEDA is oxidized under basic conditions to
generate an enamine-type electron donor, which then undergoes
SET with aryl iodide to form an aryl radical as the initiator radical
(Scheme 2). The involvement of methylene C−H bond cleavage
in the oxidation step might account for the inactivity of
methylene-deuterated DMEDA derivatives. However, no further
details regarding the radical initiation mechanism were disclosed
in their study. Our own study also excluded initiation mechanisms
1 and 2, because electrochemical measurements showed a large
potential gap (ΔE = 3.5 V) between the oxidation of either
DMEDA or the DMEDA/t-BuOK mixture and the reduction of
aryl iodide (see the Supporting Information for details).
7a,s,8d,g,13
representative one.
As a consequence, the role of this
structurally simple diamine in radical initiation attracted much
research interest. Recently, Murphy, Tuttle, and co-workers
reported their studies on the DMEDA/t-BuOK-promoted cross-
12e
coupling reactions, in which a redox-type radical initiation
pathway was proposed. However, the results of the present study
contradicted this mechanism, which prompted us to revisit the
radical initiation process in this reaction system. Through
detailed mechanistic study, a significantly different radical
initiation mechanism has been revealed.
Herein, we present the details of our mechanistic study on the
transition-metal-free coupling reaction utilizing the DMEDA/t-
BuOK system. The study was conducted using a combined
experimental and DFT computational approach, in which kinetic
analysis and isotope labeling experiments played a crucial role.
The present study revealed that an unconventional radical
initiation mechanistic network, rather than a single initiation
pathway, functioned in the reaction system. The diamine was
found to act as a hydrogen atom donor and played a dual role as
both “radical amplifier” and “radical regulator” in the radical
chain process, which is distinct from previously realized. The
transition-metal-free coupling reactions promoted by structurally
Reaction kinetics is a powerful tool for identification of
possible reaction mechanisms and for exclusion of unreasonable
14
ones. To our surprise, to date kinetic analyses have not been
conducted on these transition-metal-free cross-coupling reac-
15
tions. Aiming to disclose more details in the radical initiation
mechanism of the DMEDA/t-BuOK reaction system, we
monitored the kinetic profile of a model cross-coupling reaction,
which unexpectedly revealed the contradiction between
experimental results and this initiation mechanism.
7a,8d,g
7a,8e
related molecules (such as aminoalcohols
and diols
)
might also be understood considering this mechanism.
B
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a
Kinetic Profiles of the DMEDA-Promoted Cross-
Coupling Reaction. The coupling reaction between 4-
iodoanisole (1) and benzene was selected as a suitable model
reaction for kinetic study, which affords a good yield of 4-
methoxybiphenyl (2) in the presence of a catalytic amount of
DMEDA and excess t-BuOK at 80 °C. Our study commenced
with acquiring kinetic profiles of all components in the model
reaction. The kinetic measurement was performed under the
synthetically relevant conditions, except that a large excess of t-
BuOK (≥10 equiv) was used to maintain its concentration
constant during the reaction. It was found that the reaction
exhibited a significant induction period (ca. 20 min), after which
it completed in 2 h with 75% yield (Figure 1). Dehalogenation
Table 1. Investigation into the End-Product of Diamine
GC yield (%)
DtBEDA loading
conv. 1
(%)
b
c
entry
(mol %)
2
3
4
DtBEDA
1
2
3
4
0
20
11
27
81
94
6.7
1.0
2.8
−
4.2
−
95
81
92
17
100
300
47
39
25
51
9.9
6.8
a
Reaction conditions: 1 (0.5 mmol), t-BuOK (1.5 mmol), DtBEDA
b
(0−1.5 mmol), benzene (4 mL), sealed tube, 100 °C for 12 h. Based
c
on the amount of DtBEDA added. Remaining DtBEDA after reaction.
It was observed that the conversion of 1 was raised as the
loading of DtBEDA increased (entries 2−4), and control
experiment showed only minor background reaction under 100
°
C (entry 1). This clearly indicated that DtBEDA promoted the
cross-coupling reaction like DMEDA, albeit less efficiently.
Importantly, in all reactions performed with DtBEDA, diimime 4
was identified as the end-product (entries 2−4). This
observation implied that in the diamine-promoted cross-
coupling reaction, diamine was converted to the corresponding
diimine, and the radical initiation process might relate to this
transformation.
Figure 1. Kinetic profiles of aryl iodide 1 (blue), product 2 (green),
byproduct 3 (orange), and DMEDA (red) in the model reaction.
Reaction conditions: [DMEDA] = 22 mM, [1] = 108.5 mM, [t-BuOK]
It is notable that the diamine to diimine transformation is an
oxidation process with apparent loss of 4 electrons. Given that
the cross-coupling reaction to produce biphenyl 2 is a redox-
neutral process, while the generation of dehalogenation
byproduct 3 from 1 is a reduction process demanding 2
electrons, it is reasonable to correlate the formation of byproduct
=
1.25 M, benzene as the solvent, 80 °C.
product anisole (3) was observed to generate simultaneously
with product 2 as the major byproduct (18% yield). The kinetic
profile of DMEDA was rather unexpected. DMEDA almost
remained intact during the induction period, and was consumed
when the coupling reaction started to proceed. After the reaction
completed, the consumption of DMEDA also stopped (Figure
3
with the consumption of diamine. In the DtBEDA-promoted
reactions, the yields of byproduct 3 were roughly twice as much
as the yields of diimine 4 (Table 1); in the DMEDA-promoted
reaction, the consumed DMEDA correlated with the amount of
formed 3 in the reaction, showing a good linear relationship with
a slop of ca. 2 (Figure 2). These are in agreement with the 2:1
stoichiometry of 3 to diamine calculated based on the number of
electrons involved in the redox process.
Supported by the above results, it could be concluded that the
conversion of DMEDA to diimine 5 took place in the model
reaction system. We expected to reveal further details in this
transformation to elucidate the radical initiation mechanism in
the diamine/t-BuOK system.
1). This indicated that the decay of DMEDA was highly
dependent on the main chain reaction. This kinetic profile is
unprecedented for conventional radical initiators; it is also
inconsistent with the initiation mechanism 3. Following this
initiation mechanism, the decay of DMEDA should have no
induction period and should proceed independently regardless of
the progress of the main chain reaction. Moreover, the formation
16
of byproduct 3 could not be rationalized by this mechanism.
These contradictions prompted us to reconsider the radical
initiation mechanism of the DMEDA/t-BuOK reaction system.
Investigating the Consumption of Diamine in the
Cross-Coupling Reaction System. To collect sufficient
experimental evidence for the radical initiation mechanism, it is
essential to make clear how the diamine was consumed by
characterization of its end-product(s). However, an attempt to
identify DMEDA-related end-product failed, possibly due to its
chemical lability. Therefore, we used N,N′-di-tert-butylethanedi-
amine (DtBEDA) instead of DMEDA, expecting it to produce
more stable end-product(s) for analysis due to the bulkier N-
substituent. Prior work showed that DtBEDA was inactive in
Deuterium Labeling Experiments. To figure out how does
the diamine to diimine conversion takes place in the reaction
system, deuterium labeling experiments were conducted using
the DtBEDA model (Table 2). Three deuterium-labeled
diamines were prepared with deuterium substitution on the
ethylene bridge (DtBEDA-d ), the free NH group (DtBEDA-d ),
4
2
or both (DtBEDA-d ). In general, deuterated diamines exhibited
6
diminished activity and led to less dehalogenation byproduct 3
(Table 2, entries 1 and 2 vs Table 1, entries 3 and 4; Table 2,
entries 3 and 4 vs Table 1, entry 4), but they were still able to
promote the cross-coupling reaction. This was surprising because
it is in contrast to the literature report that the ethylene bridge
7a
12e
promoting the coupling reaction at 80 °C, but we found that it
became an active promoter at slightly elevated temperature,
enabling the end-product analysis (Table 1).
deuterated DMEDA had no activity. More importantly, the
coupling reactions employing these deuterium-labeled diamines
resulted in significant amount of deuterium incorporation at the
C
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these HAT processes, because deuterated DtBEDAs exhibited
diminished activities compared to normal DtBEDA. To date,
HAT between aryl radical and the small molecule promoter and
the remarkable effect of this process on the radical initiation
activity were not taken into consideration in the diamine-
promoted transition-metal-free cross-coupling reaction.
Kinetic Isotope Effect Study. To quantitatively assess the
effect of deuterium substitution in diamine on its activity, the
kinetic profiles of the model reaction employing deuterated
diamines as promoters were acquired. Deuterated DMEDAs
were used to perform kinetic study under unified reaction
conditions (80 °C). Three deuterium-labeled DMEDAs were
synthesized and employed to compare with normal DMEDA:
DMEDA-d with the ethylene bridge deuterated, DMEDA-d
4
6
with two N-methyl groups deuterated, and DMEDA-d with all
1
0
C−H bonds deuterated (Figure 3). The results were quite
Figure 2. Plot for the correlation of DMEDA consumption with the
generation of byproduct 3, constructed from the data in Figure 1.
a
Table 2. Deuterium Labeling Experiments
Figure 3. Time-adjusted kinetic profiles of [1] for the coupling reaction
employing deuterated DMEDA as the additive. Reaction conditions: [1]
=
100 mM, [t-BuOK] = 1.25 M, [DMEDA] = 20 mM, benzene as the
solvent, 80 °C.
intriguing. First, all deuterated DMEDAs were able to promote
the coupling reaction to full conversion in less than 3 h, again
12e
distinct from the previous report. Second, in these reactions,
deuterium incorporation on the C4-position of byproduct 3 was
observed for all deuterated DMEDAs, including the N-methyl
a
Reaction conditions: 1 (0.5 mmol), t-BuOK (1.5 mmol), deuterium
labeled DtBEDA (0.5 or 1.5 mmol), benzene (4 mL), sealed tube, 100
b
°C for 12 h. Deuterium incorporation ratio of 3 was determined by
deuterated DMEDA-d . Third, the activity of these molecules
6
2
c
GC−MS and H NMR. Based on the amount of DtBEDA added.
followed the order DMEDA-d < DMEDA-d < DMEDA <
4
10
d
Remaining DtBEDA after reaction.
DMEDA-d , in which N-methyl deuterated DMEDA-d showed
6
6
surprisingly high activity. This inverse KIE is unprecedented,
indicating that HAT from the N-methyl group of DMEDA could
also occur. Fourth, all reactions were found to have an induction
period, and the duration of induction period for deuterated
DMEDAs is considerably longer.
The present KIE study produced results in agreement with the
deuterium-labeling experiments with DtBEDA. Taken together,
we could conclude that the HAT process on diamine occurs not
only on the ethylene bridge and the NH functionality, but also on
the N-methyl groups. This accounts for the relatively low degree
of deuteration in byproduct 3 when partially deuterated diamines
were employed. The results also indicate that radical initiation in
the diamine/t-BuOK system must operate differently from
previously proposed, because all these experimental findings,
including the kinetic profile, deuterium labeling experiment, and
4
-position of dehalogenation byproduct 3, and the product
distribution (2/3) varied with the deuterium-labeling pattern of
diamine.
The deuterium labeling experiments on the DtBEDA model
provided several key clues for the initiation mechanism. First,
deuterium incorporation on C4-position of 3 clearly indicated a
hydrogen atom transfer (HAT) process between the aryl radical
and the diamine in the cross-coupling reaction, and verified the
correlation between the formation of byproduct 3 and the
consumption of diamine. Second, HAT occurred on either the
ethylene bridge or the free NH groups of diamine, as
demonstrated by the deuterium incorporation in 3 when
DtBEDAs-d and -d were employed. Third, the radical initiation
4
2
activity of the diamine/t-BuOK system was closely related to
D
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the observed inverse KIE, could not be addressed by initiation
mechanism 3. Since HAT between aryl radical and the diamine is
found to be important and the activity of the reaction system is
closely related to this process, the radical initiation process may
stand as a mechanistic network involving a series of hydrogen
atom transfer reactions, rather than a simple initiation pathway.
Mechanism for the Radical Initiation Process. At this
stage, the above results could help to draw a new radical initiation
mechanism for the DMEDA/t-BuOK system (Scheme 3). The
The mechanistic network of radical initiation is consistent with
the nonindependent consumption kinetics of diamine (Figure
1), and well accounts for the observed 1:2 stoichiometry between
diamine and byproduct 3 (Figure 2). Moreover, this network
showcases the interesting function of diamine to regulate the
radical concentration. Following pathway 1 (DMEDA → IN3 →
IN4a/b → 5/6, referred to as radical homeostasis pathway), two
aryl radicals are consumed and two are regenerated, resulting in
no net change in aryl radical count. On the other hand, following
pathway 2 (DMEDA → IN3 → IN5 → IN4a → 5, referred to as
radical proliferation pathway), one aryl radical is consumed and
three are regenerated, leading to aryl radical proliferation. Under
low [Ar·], the radical proliferation pathway predominates and the
DMEDA/t-BuOK system acts as a powerful “radical amplifier”;
under high [Ar·], the radical homeostasis pathway becomes more
important to maintain dynamic balance of the aryl radical
concentration. In the early stage of the reaction, trace amount of
the initial aryl radical could be generated by the background
reaction, as demonstrated by the control experiments (Table 1,
Scheme 3. Proposed Radical Initiation Network for the
DMEDA/t-BuOK Reaction System
17
12c
entry 1) and the literature report. According to the proposed
radical initiation network, this trace amount of aryl radical
triggers the aryl radical proliferation in the DMEDA/t-BuOK
reaction system following pathway 2, which accounts for the
induction period observed in the kinetic study.
Experimental Evidence for the Initiation Mechanism.
Several experiments were performed to provide further support
for the proposed initiation mechanism. First, the nature of some
redox-active species involved in the initiation process was
evaluated by electrochemical study. We sought to characterize
the electron-donating ability of some proposed electron donors
involved in SET process. To this end, the reduction potentials of
18
monoimine complex 7 (analogue of IN3) and diimine 4
analogue of 5) were determined (Figure 4). The result, E (7)
(
red
process commences with HAT between aryl radical and
DMEDA to afford dehalogenation product ArH. Hydrogen
abstraction from the ethylene bridge leads to radical IN1a, and
hydrogen abstraction from the NH group leads to IN1b.
Although experimental results showed there was HAT from the
N-methyl group, it does not occur at this step (according to DFT
calculation results shown in Figure 7, vide infra). Deprotonation
of both IN1a and IN1b by t-BuOK leads to radical anion IN2 (a
potent electron donor), which then undergoes SET to the aryl
iodide substrate to regenerate an aryl radical together with
monoimine IN3. The initiation process bifurcates at this point.
Following pathway 1, IN3 undergoes a second HAT with aryl
radical to produce byproduct ArH and radical intermediates
IN4a and IN4b. HAT from the methylene of IN3 leads to IN4a,
while HAT from the N-Me on the secondary amine of IN3 leads
to IN4b. HAT from the imine N-Me is disfavored (according to
DFT calculation). Following pathway 2, IN3 is deprotonated by
t-BuOK to form enamide IN5, which serves as an electron donor
to undergo SET to the ArI substrate, producing a new aryl
radical, as well as radical IN4a. The two pathways converge at
radical IN4a, which is further deprotonated to form radical anion
IN6a. Finally, IN6a undergoes SET to the ArI substrate and
produces diimine 5. It is reasonable to assume that the fate of
IN4b is similar to that of IN4a, in which deprotonation and SET
generate a new aryl radical as well as diimine 6. In the proposed
initiation mechanism, all deprotonation steps are thought to be
irreversible, because t-BuOH was found to have no inhibitory
effect on the reaction (see the Supporting Information for
details).
Figure 4. Reduction potentials for the analogues of key redox-active
species measured by differential pulse voltammetry (DPV).
= −2.1 V and E (4) = −2.0 V vs Fc+/0, suggests that the
red
oxidation potentials of the proposed electron donors, IN2 and
IN6a, are close to −2.0 V. The small potential gap (ΔE ≈ 0.9 V)
between the oxidation of these electron donors and the reduction
of iodoarene 1 provides support for the SET processes in the
proposed initiation mechanism.
Second, the crucial role of intermediate IN3, the bifurcation
point in the proposed mechanism, was confirmed by
independent experiment with its analogue, compound 7. It was
found that monoimine 7 alone could promote the model
coupling reaction, producing the coupling product 2 in 57% yield
together with 15% yield of 3 (Figure 5). Diimine 4 was detected
in significant amount as the end-product of 7, which is in line
with the proposed initiation pathways IN3 → 5. Notably, as
demonstrated by operando IR spectroscopy, the reaction
promoted by monoimine 7 exhibited no induction period,
which is distinct from the reaction promoted by DMEDA
(Figure 5). This provides support for the proposed initiation
mechanism, in which monoimine IN3 directly enables the radical
proliferation pathway (Scheme 3).
E
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result in a higher barrier for HAT. In contrast, deuteration on the
N-Me groups of DMEDA slows down the IN3 → IN4b process
and thus increases the steady state concentration of IN3, which
favors the radical proliferation pathway. This is in agreement with
the observation that N-Me deuterated DMEDAs exhibited a
better activity compared with DMEDAs without N-Me
deuteration (a quantitative understanding of this phenomenon
is shown later).
Computational Study. Density functional theory (DFT)
20
computational study was conducted to confirm the proposed
initiation mechanistic network. The reactions depicted in
21
Scheme 3 were calculated at the M06-2X /6-311+G(d,p)
level of theory using the CPCM method to evaluate the solvation
effect in benzene, in which phenyl group was used as the Ar
substituent. The potential energy surface was established based
on calculated Gibbs free energies in benzene (Figure 7).
It was found that HAT between phenyl radical (Ph·) and
DMEDA could occur at two positions: hydrogen abstraction
from the ethylene bridge via TS1a produces carbon-centered
radical IN1a with an activation barrier of 11.4 kcal/mol;
hydrogen abstraction from the NH group via TS1b produces
nitrogen-centered radical IN1b with slightly elevated activation
barrier, 11.8 kcal/mol. HAT from the N-Me group of DMEDA
via TS1c has a greater activation barrier (14.5 kcal/mol) and is
not feasible. Radical intermediates IN1a and IN1b then undergo
proton abstraction with t-BuOK via TS2a and TS2b,
respectively, to afford the same intermediate IN2′, which has
the feature of a radical anion and serves as an electron donor.
Subsequent SET between IN2′ and iodobenzene (PhI) to form
iodobenzene radical anion/t-BuOH complex IN7 and mono-
imine IN3 is exergonic by 16.5 kcal/mol, rendering the overall
process (IN1a/1b → IN3) thermodynamically favored. The
initiation network bifurcates at IN3. Following pathway 1, a
second HAT occurs between Ph· and the methylene group in
IN3 to form radical IN4a via TS3a with an activation energy
barrier of 11.5 kcal/mol. The following proton abstraction by t-
BuOK afforded intermediate IN6a′. The electron transfer
between IN6a′ and PhI to form IN7 and diimine 5 is endergonic
by 7.8 kcal/mol, but subsequent C−I bond cleavage of IN7
makes the overall process exergonic by 6.2 kcal/mol. A parallel
route in pathway 1, in which HAT between Ph· and IN3 occurs at
the N-Me of the secondary amine via TS3b, is also evaluated by
DFT calculation. This event produces radical IN4b, which then
undergoes deprotonation and electron transfer to form diimine 6
resembling IN4a. Although this route has a higher activation
energy barrier compared with HAT from the methylene in IN3
Figure 5. Time-adjusted kinetic profiles of [1] for the coupling reaction
employing DMEDA (blue) and monoimine 7 (red) as the additive.
Reaction conditions: [7] = 22 mM, [1] = 100 mM, [t-BuOK] = 1.25 M,
benzene as the solvent, 80 °C.
Third, it was found that, by addition of trace amount of iodine
to the reaction system, the induction period was remarkably
shortened and acceleration of the reaction was observed. The
magnitude of this positive effect depends on the amount of
iodine added: addition of 0.2 mol % I resulted in initiation of the
2
reaction within 1 min without interfering with the reaction
kinetics (Figure S12), while addition of 1−2 mol % I initiated
2
the reaction immediately and led to reaction acceleration (Figure
6
). Control experiment revealed that I alone (without diamine)
2
(
12.3 vs 11.5 kcal/mol), it is important because it accounts for
the experimentally observed HAT from the N-Me group of
DMEDA. These two parallel routes constitute pathway 1 and
they proceed simultaneously. In pathway 2, deprotonation of
IN3 by t-BuOK via TS5 to form enamide IN5′ is endergonic by
Figure 6. Time-adjusted plot of the conversion of 1 in the model
reaction with different amount of I added. Reaction conditions: [1] =
2
100 mM, [DMEDA] = 20 mM, [t-BuOK] = 1.25 M, benzene as the
solvent, 80 °C.
1
1.4 kcal/mol with an activation energy barrier of 14.9 kcal/mol.
SET from IN5′ to PhI is endergonic by 12.8 kcal/mol, producing
radical IN4a and iodobenzene radical anion/t-BuOH complex
IN7. In conjugation with subsequent C−I bond cleavage, this
process is slightly exergonic by 1.2 kcal/mol. Then, IN4a could
be further converted to diimine 5 following pathway 1. The
potential energy surface indicates that pathway 1 is favored over
pathway 2 when sufficient concentration of aryl radical is present.
The calculated potential energy surface is in good agreement
with all experimental observations and provides support for the
proposed mechanism: (i) the HAT processes between aryl
radical and DMEDA could occur on multiple sites of the diamine
could not initiate the reaction. Given that I could convert an
amine to imine, this iodine initiation experiment provides
support for the proposed initiation mechanism: DMEDA could
2
1
9
be oxidized to monoimine IN3 by the added I , and IN3 initiates
2
the reaction easily.
Finally, observations in our deuterium labeling experiments
and the KIE study also strongly support the proposed radical
initiation network. Deuteration on ethylene bridge and amine
NH group of the diamine makes it less effective in initiating the
coupling reaction, because primary kinetic isotope effect would
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Article
Figure 7. Gibbs free energy (ΔGsolv 298K) profile for the initiation pathways calculated at the M06-2X/6-311+G(d,p) level of theory.
and are feasible both thermodynamically and kinetically; (ii) the
electron-rich intermediates (IN2′, IN6a′, IN6b′, and IN5′,
correspond to IN2, IN6, and IN5 in Scheme 3) are able to
undergo SET with the aryl iodide; (iii) the initiation pathways
and the main chain reaction proceed simultaneously, because the
activation barriers of HAT (between aryl radical and DMEDA)
and radical addition (between aryl radical and benzene) are
network. Bringing the proposed initiation mechanism and the
main chain reaction together, a kinetic model for the complete
DMEDA/t-BuOK reaction system is established (Scheme 4).
The model comprises two parts, the initiation network and the
cross-coupling part, where chain initiation and propagation steps
were included, respectively. The chain termination pathway is
assumed to be the homocoupling of the reactive aryl radical,
22
similar (11.4/11.8 vs 15.2 kcal/mol). Although the HAT
⧧
process is more facile than radical addition as judged by ΔG , the
9
−1 −1 23
which has a bimolecular rate constant of >10 M ·s .
Although this kinetic model seems complicated, clear and
simple rate laws could be derived by applying steady-state
low concentration of DMEDA (ca. 20 mM) and high
concentration of benzene (as solvent) make the main chain
reaction favored.
24
approximation to all reactive intermediates. Solving for the
Kinetic Studies. In addition to DFT calculation, reaction
kinetics provided important support for this radical initiation
concentration of the key radical species, [Ar·], one obtains:
2
2
2
k k [t‐BuOK] + 4k
k
k k [t‐BuOK][DMEDA] −k k [t‐BuOK]
t
2
HAT1 HAT2
t
2
t 2
[
Ar·] =
2
kHAT2kt
(1)
(3)
d[ArPh]
=
kadd[PhH][Ar·]
The rate laws for aryl iodide consumption and product formation
are
dt
d[ArI]
dt
−
≈ kadd[PhH][Ar·] + 2kHAT1[DMEDA][Ar·]
d[ArH]
≈ 2kHAT1[DMEDA][Ar·]
(4)
(2)
dt
G
DOI: 10.1021/jacs.6b03442
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Article
Scheme 4. Kinetic Model for the DMEDA/t-BuOK Cross-
Coupling Reaction System
analysis was performed for the model reaction. A series of initial
rate experiments were conducted to establish the dependence of
reaction rate on each component. It was found that the initial rate
based on consumption of 1 exhibited zero-order in [1], in
accordance with eq 5 that no term relates to [1] exists in the rate
law. The reaction rate showed positive orders in both [DMEDA]
and [t-BuOK], which was in agreement with eq 5. Gratifyingly,
the measured rate dependence fit very well to eq 5 (Figure 8),
indicating that the reaction kinetics is subject to the rate law
derived from the present kinetic model.
Figure 8. Dependence of the initial rate on [DMEDA] (A) and [t-
BuOK] (B). Reaction conditions: (A) [DMEDA] = 10−100 mM, [1] =
1
00 mM, [t-BuOK] = 1.25 M; (B) [t-BuOK] = 0.125−1.25 M, [1] = 100
mM, [DMEDA] = 20 mM; benzene as the solvent, 80 °C.
Furthermore, comparison between eqs 6 and 7 shows that,
following the proposed mechanism, the generation of byproduct
ArH (3) is more directly related to [DMEDA] than product
ArPh (2). By dividing eq 7 with eq 6, a simple linear relationship
between [ArH] to [ArPh] ratio and [DMEDA] emerged:
Substitution of eq 1 into eqs 2−4 and treating [PhH] as constant
give the simplified rate laws:
d[ArI]
dt
−
≈ (1 + c[DMEDA])·
[
ArH]
d[ArH]/dt
d[ArPh]/dt
=
= c[DMEDA]
2
2
[ArPh] initial
(
a [t‐BuOK] + b[t‐BuOK][DMEDA]
a[t‐BuOK])
(11)
Thus, the model reactions with different [DMEDA] were
performed and the [3]/[2] ratios were determined at low
conversion (<30%). It was found that the [3]/[2] ratio exhibited
a good linear relationship with [DMEDA] (Figure 9), which is in
good agreement with eq 11 and demonstrates the importance of
DMEDA in the HAT process.
−
(5)
(6)
d[ArPh]
2
2
=
a [t‐BuOK] + b[t‐BuOK][DMEDA]
a[t‐BuOK]
dt
−
d[ArH]
≈
c[DMEDA]·
dt
2
2
(
a [t‐BuOK] + b[t‐BuOK][DMEDA]
−
a[t‐BuOK])
(7)
where a, b, and c are constants composed of various rate
constants:
k2kadd[PhH]
a =
2
kHAT2
(8)
b = k
k k 2[PhH]2
kHAT2kt
HAT1 2 add
(9)
2
kHAT1
c =
kadd[PhH]
(10)
These rate laws reveal explicit relationships between the
reaction kinetics and the concentrations of both DMEDA and t-
BuOK. Aiming to verify the radical initiation mechanism, kinetic
Figure 9. Relationship between the ratio of anisole (3) to product (2)
and [DMEDA]. Reaction conditions: [1] = 100 mM, [DMEDA] =
28.5−250 mM, [t-BuOK] = 1.25 M, benzene as the solvent, 80 °C.
H
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Article
Finally, the inverse kinetic isotope effect observed for N-Me
deuterated DMEDAs (Figure 3) could be well rationalized by the
derived rate laws. Because deuterium substitution on N-Me
group of DMEDA does not affect HAT on the ethylene bridge
The discovery that aryl radical could also interact with the small
molecule promoter and thus modulate the activity of the reaction
system represents a novel and unprecedented radical initiation
mode, which would be taken into account when studying related
reactions. Also, as learned from this study, a hydrogen atom
donor moiety with a neighboring XH bond might be the key
structural feature of a successful promoter that efficiently initiates
the transition-metal-free coupling reaction. Diols, aminoalcohols,
alkyl alcohols, hydrazine derivatives, and amino acids fall into this
category and were all proved to be efficient promoters in this
reaction. We expect the insight obtained from this study to help
to understand the mechanism of many relevant reactions, as well
as to guide the development of more efficient radical chain
reactions for synthesis.
and the NH group, DMEDA-d exhibits the same rate constant
6
kHAT1 as normal DMEDA. However, in pathway 1, rate constant
for HAT on the N-Me group of IN3, kHAT2b, will decrease
dramatically due to primary KIE. Therefore, the DMEDA-d /t-
6
BuOK reaction system has the same kHAT1 but decreased kHAT2
compared with DMEDA/t-BuOK system. From a mathematic
point of view, in the rate laws the term kHAT2 always exists in
denominator (eqs 5−10); thus, a smaller k
results in a
HAT2
greater reaction rate. From a mechanistic viewpoint, the slower
HAT in pathway 1 leads to a higher steady-state concentration of
IN3 in the chain process, which subsequently results in an
accelerated radical proliferation pathway 2. The observation that
DMEDA-d10 is more active than DMEDA-d4 could be
rationalized by the same principle. This intriguing inverse kinetic
isotope effect is difficult to understand without considering this
initiation network.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b03442.
■
S
Experimental procedures, kinetic data, details for rate law
deduction, and computational results (PDF)
Detailed kinetic analysis showed that the features of the
DMEDA/t-BuOK reaction system perfectly matched those
predicted from the kinetic model. This provides important
support for the proposed radical initiation network.
AUTHOR INFORMATION
Corresponding Author
*Leijiao@mail.tsinghua.edu.cn
■
CONCLUSION
■
In this article, the DMEDA/t-BuOK reaction system was
selected as a representative model to study the unusual radical
initiation mechanism in transition-metal-free cross-coupling
reactions developed in recent years. Through a combined
experimental and DFT computational study, the radical initiation
mechanism in the diamine-promoted cross-coupling reaction
was carefully reinvestigated. The results revealed an unconven-
tional radical initiation network in the DMEDA/t-BuOK system,
which could replace the previously proposed radical initiation
mechanism.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The Thousand Talents Plan for Young Professionals and the
National Natural Science Foundation of China (Grant No.
■
2
1390403) are acknowledged for financial support. We thank
Prof. Ming-Tian Zhang for helpful discussions and suggestions.
The technology platform of CBMS and the Tsinghua Xuetang
Talents Program are acknowledged for providing instrumenta-
tion and computational resources.
The key question regarding the initiation mechanism is the
role of diamine in the reaction. Preliminary kinetic study
excluded the role of DMEDA as a catalyst or a radical initiator,
and ruled out the simple redox-type initiation pathway proposed
in previous study. End-product analysis, deuterium labeling
experiments, KIE study, electrochemical study, intermediate
synthesis, and initiation experiments suggested a novel radical
initiation mechanistic network involving hydrogen atom transfer
between DMEDA and the aryl radical. In this network, the
diamine does not directly promote the generation of aryl radical,
but plays a dual role: first, it enables proliferation of the initial aryl
radical to initiate the radical chain reaction (as a radical
amplifier); second, it regulates the concentration of the aryl
radical by HAT-based processes (as a radical regulator). This has
been further verified by DFT calculation and kinetic analysis. In
particular, kinetic analysis was performed on the transition-
metal-free cross-coupling reaction for the first time, which
provided significant support for the reaction mechanism.
Interestingly, the revealed radical initiation network is more
complicated than the main chain reaction. This mechanistic
network and the subtle role of such simple diamine molecule in
the radical chain reaction are rather uncommon.
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