Email: laoniulyb@shsmu.edu.cn; chunsen.li@fjirsm.ac.cn;
fengcg@shutcm.edu.cn
Keywords: aggregated state, ionic insertion, solvent-free and
catalyst-free, atom-and step-economy
Abstract: Molecular aggregation affects the electronic interactions
between molecules and has emerged as a powerful tool in material
science. Molecular aggregation finds wide applications in the research
of new physical effects; however, its value for chemical reaction
development has been far less explored. Herein, we report the
development of aggregation-enabled alkene insertion into carbon–halogen
bonds. The spontaneous cleavage of C–X (X = Cl, Br, or I) bonds
generates an intimate ion pair, which can be quickly captured by alkenes
in the aggregated state. Additional catalysts or promoters are not
necessary under such circumstances, and
solvent quenching experiments
indicate that the aggregated state is critical for initiating such
sequences. The ionic insertion mode and the intimate ion pair mechanism
are supported by mechanistic studies, density functional theory
calculations, and symmetry-adapted perturbation theory analysis. Results
show that the non-aggregated state may quench the transition state and
terminate the insertion process.
Introduction
Since Tang and co-worker’s seminal work in 2001,1aggregate science has emerged as a productive area of molecular
science.2-4 Unlike previous studies that focused on
the properties of isolated molecules, the new perspective brings us the
novel characteristics enabled by molecular aggregates. Interactions
between molecules in aggregates induce unique physical changes, such as
aggregation-induced emission5 and
self-assembly-induced crystallization,6 in the system,
finding wide applications in biology and material sciences. Therefore,
it is an obvious logical extension that the increased interactions
between molecules in aggregates may induce chemical reactions between
corresponding molecules. While studying the dissociation of
HCl(H2O)4 at ultracold temperatures,
Birer and co-workers7,8 proposed a mechanism
of aggregation-induced dissociation. Although this physical chemistry
study is instructive, it falls short of developing synthetically useful
chemical processes.
In solvent-free reactions, reactants are in close contact with each
other, and such an aggregated state may benefit the reaction. However,
while considerable attention has been paid to the green and sustainable
features of this type of system,9-10 its potential to
promote reactions has been neglected. Therefore, we recently initiated a
project to discover novel synthetic methods guided by the aggregated
state concept (Figure 1A).
Owing to the diverse and rich reaction chemistry associated with
carbon–halogen (C–X) bonds, organohalides are crucial in synthetic
chemistry.11-15 Moreover, they are prevalent
structural subunits in numerous important natural products and
pharmaceuticals.16-19 Although halides can be obtained
by numerous methods, efficient, practical, and green methods are
currently being developed.20-24 Carbohalogenative
1,2-difunctionalization of double bonds with organohalides has emerged
as an appealing method with excellent atom economy, step economy, and
versatility.25-28 Insertion of double bonds into C–X
bonds is among the most direct and efficient methods for generating C–C
and C–X bonds simultaneously.
Figure 1. Insertion of alkene into carbon–halogen bonds.
To initiate the insertion process, a suitable catalyst or promoter for
disconnecting C–X bonds has become an essential tool and rendered three
viable pathways (Figure 1B). For C(sp2)–X bonds, a
palladium-29-36 and
nickel-37-41catalyzed oxidative addition/migratory
insertion/reductive elimination sequence is a successful route (Figure
1B-i). However, extending this method to the insertion of
C(sp3)–X bonds would be problematic owing to the
competition of β -H elimination. A complementary strategy for
C(sp3)–X insertion is atom transfer radical addition
(ATRA) reaction (Figure 1B-ii).42-45 When initially
proposed by Kharasch46 in the 1940s, this type of
reaction was limited to stoichiometric quantities of harmful oxidants,
organotin reagents, and organoboron reagents as radical
initiators.47-48 Subsequently, a series of
metal-catalyzed49-50 or
photocatalytic51-55 ATRA reactions employing
haloalkanes were reported. Despite considerable advancements, some major
limitations and challenges remain in the methods based on the above
mechanism; for example, the need for expensive transition catalysts, the
strict requirements of the experimental operations, insufficient
accommodation of some reactive functional groups, and difficulty
associated with the use of alkyl chloride substrates.
Third is insertion via the heterolytic cleavage of C–X bonds
(Figure 1B-iii). However, although such ionic reactions have a long
history, only alkyl C–Cl bond
insertion with limited substrate scope has been presented and literature
reports in this regard are sparse.56-59 Lack of
interest might be ascribed to the challenge in controlling
carbocation-involved E1 elimination and cationic
polymerization.60-62 Furthermore, insertion into more
reactive C–Br and C–I via this approach remains elusive.
Therefore, developing creative strategies that can address the
limitations to provide new opportunities to this research area is highly
desirable.
We envisioned that an aggregated state could enable spontaneous cleavage
of alkyl C–X bonds to initiate ionic insertion
reactions.63 If the reaction is performed under an
aggregated state, it is possible to capture a transient ion pair through
the contact touch with alkenes.64 Furthermore, the
cleavage of the C–X bond may be facilitated by alkenes through the
formation of a π complex65 or the stabilization of the
generated cations to onium ions, which is not stable under dilute
solution state (Figure 1C-i).66 This promotes the
insertion of the desired alkene without transition metal catalysts.
Compared with ionic insertion through Lewis-acid catalysis, the contact
nature under an aggregated state may facilitate a fast cascade process,
which avoids competitive E1 elimination reactions and cationic
polymerization.67-68
Herein, we report the development of aggregation-enabled alkene
insertion into carbon–halogen bonds (Figure 1C-ii). The insertion into
C–Cl, C–Br, and C–I bonds can be realized with the completed atom
economy and high step economy under catalyst-free conditions.
Specifically, the excellent compatibility of functional groups indicates
that this methodology has potential applications in the field of organic
synthesis.
Results
Reaction Development. After extensive optimization, the
reaction of alkene 1a and benzyl chloride 2a afforded
the highest yield of 93% at 100°C for 5 h in an aggregated state (Table
1, entry 1). Decreasing the reaction temperature considerably reduced
the conversion of 1a and 2a , yielding only 7% of3aa . The yield did not improve by increasing the temperature
(entries 7 and 9) or by adjusting the ratio of 1a and2a (entries 10 and 11). Further, the solvent effect of this
process was tested. Thus, no product formation was observed in either
polar or nonpolar solvents. We believe that nonpolar solvents such as
toluene and n -hexane (entries 1 and 2, respectively) increase the
free energies of the carbocation transition state, raising the
activation energies.64 Conversely, in polar solvents
(entries 3–6), the positive charge of the carbocations would be
dispersed by coordination with the solvent, reducing the
electrophilicity of benzyl cations68. The cage effect
of the solvent can also block the reaction by reducing the collision
probability of alkenes and benzyl cations.71 A high
yield was maintained during the reaction that proceeded in the dark,
indicating a nonphotocatalytic process (entry 13).
Table 1. Effect of reaction parameters on the insertion of
alkenes into C–Cl bonds.