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\begin{document}

\title{Aggregation Enabled Alkene Insertion into Carbon--Halogen Bonds}



\author[1]{Meng-Yao Li}%
\author[1]{Xiao-Mei Nong}%
\author[2]{Han Xiao}%
\author[1]{Ao Gu}%
\author[1]{Shuyang Zhai}%
\author[1]{Jiatong Li}%
\author[3]{Ge Zhang}%
\author[3]{Ze-Jian Xue}%
\author[1]{Yingbin Liu}%
\author[2]{Chunsen Li}%
\author[4]{Guo-Qiang Lin}%
\author[4]{Chen-Guo Feng}%
\affil[1]{Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital}%
\affil[2]{Chinese Academy of Sciences Fujian Institute of Research on the Structure of Matter}%
\affil[3]{Shanghai Institute of Organic Chemistry Chinese Academy of Sciences}%
\affil[4]{Shanghai University of Traditional Chinese Medicine}%


\vspace{-1em}



  
  \date{June 09, 2024}


\begingroup
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\selectlanguage{english}
\begin{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.%
\end{abstract}%



\sloppy


Aggregation-enabled Alkene Insertion into Carbon--Halogen Bonds

Meng-Yao Li,\textsuperscript{1,2,4} Xiao-Mei Nong,\textsuperscript{1}Han
Xiao,\textsuperscript{3} Ao Gu,\textsuperscript{1} Shuyang
Zhai,\textsuperscript{1} Jiatong Li,\textsuperscript{1} Ge
Zhang,\textsuperscript{4} Ze-Jian Xue,\textsuperscript{4} Yingbin
Liu,\textsuperscript{1*} Chunsen Li,\textsuperscript{3*} Guo-Qiang
Lin,\textsuperscript{2,4} Chen-Guo Feng\textsuperscript{2,4*}

\textsuperscript{1}Shanghai Cancer Institute, Department of
Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao
Tong University School of Medicine, Shanghai, China.

\textsuperscript{2}The Research Center of Chiral Drugs, Innovation
Research Institute of Traditional Chinese Medicine, Shanghai Frontiers
Science Center for Traditional Chinese Medicine Chemical Biology,
Shanghai University of Traditional Chinese Medicine, Shanghai, China.

\textsuperscript{3}State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou, China.

\textsuperscript{4}CAS Key Laboratory of Synthetic Chemistry of Natural
Substances, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai,
China.

\textbf{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,\textsuperscript{1}aggregate science has emerged as a productive
area of molecular science.\textsuperscript{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
emission\textsuperscript{5} and self-assembly-induced
crystallization,\textsuperscript{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(H\textsubscript{2}O)\textsubscript{4} at ultracold temperatures,
Birer and co-workers\textsuperscript{\textbf{7,8}} 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,\textsuperscript{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.\textsuperscript{11-15} Moreover, they are prevalent
structural subunits in numerous important natural products and
pharmaceuticals.\textsuperscript{16-19} Although halides can be obtained
by numerous methods, efficient, practical, and green methods are
currently being developed.\textsuperscript{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.\textsuperscript{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.

\textbf{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(sp\textsuperscript{2})--X bonds, a
palladium-\textsuperscript{29-36} and
nickel-\textsuperscript{37-41}catalyzed oxidative addition/migratory
insertion/reductive elimination sequence is a successful route (Figure
1B-i). However, extending this method to the insertion of
C(sp\textsuperscript{3})--X bonds would be problematic owing to the
competition of \selectlanguage{greek}\emph{β} -\selectlanguage{english}H elimination. A complementary strategy for
C(sp\textsuperscript{3})--X insertion is atom transfer radical addition
(ATRA) reaction (Figure 1B-ii).\textsuperscript{42-45} When initially
proposed by Kharasch\textsuperscript{46} in the 1940s, this type of
reaction was limited to stoichiometric quantities of harmful oxidants,
organotin reagents, and organoboron reagents as radical
initiators.\textsuperscript{47-48} Subsequently, a series of
metal-catalyzed\textsuperscript{49-50} or
photocatalytic\textsuperscript{51-55} 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 \emph{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.\textsuperscript{56-59} Lack of interest might be ascribed to the
challenge in controlling carbocation-involved E1 elimination and
cationic polymerization.\textsuperscript{60-62} Furthermore, insertion
into more reactive C--Br and C--I \emph{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.\textsuperscript{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.\textsuperscript{64} Furthermore, the
cleavage of the C--X bond may be facilitated by alkenes through the
formation of a \selectlanguage{greek}π \selectlanguage{english}complex\textsuperscript{65} or the stabilization of the
generated cations to onium ions, which is not stable under dilute
solution state (Figure 1C-i).\textsuperscript{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.\textsuperscript{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

\textbf{Reaction Development.} After extensive optimization, the
reaction of alkene \textbf{1a} and benzyl chloride \textbf{2a} afforded
the highest yield of 93\% at 100\selectlanguage{ngerman}°C for 5 h in an aggregated state (Table
1, entry 1). Decreasing the reaction temperature considerably reduced
the conversion of \textbf{1a} and \textbf{2a} , yielding only 7\%
of\textbf{3aa} . The yield did not improve by increasing the temperature
(entries 7 and 9) or by adjusting the ratio of \textbf{1a}
and\textbf{2a} (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 \emph{n} -hexane (entries 1 and 2, respectively) increase
the free energies of the carbocation transition state, raising the
activation energies.\textsuperscript{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 cations\textsuperscript{68}. The cage effect
of the solvent can also block the reaction by reducing the collision
probability of alkenes and benzyl cations.\textsuperscript{71} A high
yield was maintained during the reaction that proceeded in the dark,
indicating a nonphotocatalytic process (entry 13).

\textbf{Table 1.} Effect of reaction parameters on the insertion of
alkenes into C--Cl bonds.\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Entry\textsuperscript{a}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Solvent\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
T (\selectlanguage{ngerman}°C)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
t (h)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Conversion of \textbf{1a} (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Yield of \textbf{3aa} (\%)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Toluene\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
n.d.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
n-hexane\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
n.d.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CH\textsubscript{2}Cl\textsubscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
n.d.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
DMF\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
n.d.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MeCN\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
n.d.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
THF\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
n.d.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
none\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
93\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
none\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
80\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
24\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
7\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
none\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
120\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
10\textsuperscript{b}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
none\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
97\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
73\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
11\textsuperscript{c}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
none\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
81\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12\textsuperscript{d}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
none\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
90\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
13\textsuperscript{e}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
none\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
91\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{a}Reaction conditions: \textbf{1a} (0.3 mmol) and
\textbf{2a} (0.9 mmol) at 100 \selectlanguage{ngerman}°C for 5 h under air. Corrected GC yields
using \emph{n}-dodecane as an internal standard were reported. n.d. =
not detected. \textsuperscript{b}\textbf{1a/2a} = 1:1.
\textsuperscript{c}\textbf{1a/2a} = 1:2. \textsuperscript{d}Under argon.
\textsuperscript{e}In dark.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{a}Reaction conditions: \textbf{1a} (0.3 mmol) and
\textbf{2a} (0.9 mmol) at 100 \selectlanguage{ngerman}°C for 5 h under air. Corrected GC yields
using \emph{n}-dodecane as an internal standard were reported. n.d. =
not detected. \textsuperscript{b}\textbf{1a/2a} = 1:1.
\textsuperscript{c}\textbf{1a/2a} = 1:2. \textsuperscript{d}Under argon.
\textsuperscript{e}In dark.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{a}Reaction conditions: \textbf{1a} (0.3 mmol) and
\textbf{2a} (0.9 mmol) at 100 \selectlanguage{ngerman}°C for 5 h under air. Corrected GC yields
using \emph{n}-dodecane as an internal standard were reported. n.d. =
not detected. \textsuperscript{b}\textbf{1a/2a} = 1:1.
\textsuperscript{c}\textbf{1a/2a} = 1:2. \textsuperscript{d}Under argon.
\textsuperscript{e}In dark.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{a}Reaction conditions: \textbf{1a} (0.3 mmol) and
\textbf{2a} (0.9 mmol) at 100 \selectlanguage{ngerman}°C for 5 h under air. Corrected GC yields
using \emph{n}-dodecane as an internal standard were reported. n.d. =
not detected. \textsuperscript{b}\textbf{1a/2a} = 1:1.
\textsuperscript{c}\textbf{1a/2a} = 1:2. \textsuperscript{d}Under argon.
\textsuperscript{e}In dark.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{a}Reaction conditions: \textbf{1a} (0.3 mmol) and
\textbf{2a} (0.9 mmol) at 100 \selectlanguage{ngerman}°C for 5 h under air. Corrected GC yields
using \emph{n}-dodecane as an internal standard were reported. n.d. =
not detected. \textsuperscript{b}\textbf{1a/2a} = 1:1.
\textsuperscript{c}\textbf{1a/2a} = 1:2. \textsuperscript{d}Under argon.
\textsuperscript{e}In dark.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textsuperscript{a}Reaction conditions: \textbf{1a} (0.3 mmol) and
\textbf{2a} (0.9 mmol) at 100 \selectlanguage{ngerman}°C for 5 h under air. Corrected GC yields
using \emph{n}-dodecane as an internal standard were reported. n.d. =
not detected. \textsuperscript{b}\textbf{1a/2a} = 1:1.
\textsuperscript{c}\textbf{1a/2a} = 1:2. \textsuperscript{d}Under argon.
\textsuperscript{e}In dark.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\par\null

\textbf{Substrate Scope.} The scope of the reaction under optimized
conditions was investigated. Various aryl ethylenes were tested as
nucleophiles, and the corresponding ionic insertion products delivered
moderate to excellent reaction yields (Figure 2A). For substrates with
substitutions on the \emph{para} position, electron-deficient substrates
usually gave higher reaction yields, which were primarily ascribed to
their relatively low reactivity toward the newly generated benzyl
chloride. Further, excellent functional-group tolerance was observed
(\textbf{3ac--3ae} ). For example, the reaction with substrates bearing
--OCF\textsubscript{3} and --SCF\textsubscript{3} substitutions, often
embedded in pharmaceutical and agrochemical products, afforded the
corresponding products in excellent yields (\textbf{3af} and\textbf{3ag}
). The --Br (\textbf{3ae} ), --I (\textbf{3ap} ), alkyne (\textbf{3aj}
), and boronate (\textbf{3an} and \textbf{3ao} ) substitutions, which
may have been incompatible in previous transition-metal catalyzed
processes, were all well tolerated, thereby providing handles for
further derivation. Some reactive functional groups in conventional
synthetic methods, including aryl esters, aldehydes, carboxyl, and
benzyl chloride groups, were well accommodated (\textbf{3ak--3am} and
\textbf{3aq} ). Furthermore, functional groups at\emph{meta} or
\emph{ortho} positions of the phenyl ring were acceptable
(\textbf{3ar--3av} ) and showed a similar electronic preference compared
with the \emph{para} substitutions.

Subsequently, the feasibilities of benzyl chlorides \textbf{2} were
explored, beginning with the examination of the electronic effects of
the substituents (Figure 2B). After comparing \textbf{3ba}
and\textbf{3be} , we found that the electron-donating substituents at
the\emph{para} position increased the reaction yield. The
electron-donating conjugation effect on the aromatic ring decreased the
activation energy of the heterolytic cleavage of the C--Cl bond. The
substrates featuring halogen atom, such as --F, --Cl, --Br, and --I, at
the phenyl ring (\textbf{3ba--3bd} ), reacted with styrene to afford
products in good yields.

Further, steric effect was analyzed by changing the position of the
methyl group. This showed that the steric effect of an aryl ring has a
slight influence on the proposed reaction. The\emph{ortho}
-methyl-substituted substrate provided the product in 92\% yield
(\textbf{3bg} ). In addition, long alkyl chains provided products
(\textbf{3bi} and \textbf{3bj} ) in moderate yields.

\textbf{Figure 2.} Insertion of alkenes into C--Cl
bonds.\textsuperscript{a}Reaction conditions: \textbf{1} (0.6 mmol)
and\textbf{2} (1.8 mmol) at 80 °C--120 °C for 1--5 h under air.
R\textsuperscript{1} = 1-phenylethyl, R\textsuperscript{2} = benzhydryl,
Ar\textsuperscript{1} = Ph, Ar\textsuperscript{2} =
4-CF\textsubscript{3}-Ph, and Ar\textsuperscript{3} = 4-MeO-Ph. SI
provides the detailed conditions for each substrate.\textsuperscript{b}A
gram scale reaction was performed under air using\textbf{1} (10.0 mmol).

Diphenylmethane has highly important applications in the synthesis of
bioactive compounds;\textsuperscript{72} thus, a series of diarylmethyl
chlorides as substrates were investigated. Owing to the stability of a
carbocation, excellent compatibility of these substrates was observed
for the proposed reaction. Both electron-withdrawing (\textbf{3bl} ) and
electron-donating (\textbf{3br} ) substituents underwent insertion
reactions with good yields. A heteroaromatic thienyl group (\textbf{3bq}
) was also well tolerated in the reaction. In addition to benzyl
chlorides, primary and secondary allyl chlorides were verified as
suitable coupling partners (\textbf{3bs} and \textbf{3bt} ).
Furthermore, the scalability of the proposed reaction was evaluated by
performing a reaction with 10.0 mmol of \textbf{1b} . An improved yield
of 95\% was obtained compared with small-scale trials.

\textbf{Figure 3.} Insertion into C--Br and C--I
bonds.\textsuperscript{a}Ar\textsuperscript{2} =
4-CF\textsubscript{3}-Ph. SI provides the detailed conditions for each
substrate.

We extended the reaction scope of benzyl bromides and iodides (Figure
3). The insertion reaction was explored using styrene as the
nucleophile. Alkyl bromide \textbf{5aa} was successfully obtained with a
satisfactory yield under standard reaction conditions. Introduction of
an electron-withdrawing substituent decreased the reaction yield
(\textbf{5ab} ), which can be attributed to an increased difficulty for
the heterolytic cleavage of the C--Br bond. The replacement of methyl
with ethyl provided \textbf{5ac} but with a slight reduction in yield.
When bromodiphenylmethane was used as the electrophile, the yield
(\textbf{5ad} ) was improved because C--Br bonds are easier to cleave
owing to the conjugation effect. Halogens on the alkyl chains were well
tolerated (\textbf{5ae} and \textbf{5af} ), and their insertion into
unactivated carbon--halogen bonds was not observed. Further, benzyl
iodides were suitable substrates in the insertion reaction (\textbf{5ag}
), for which the insertion process was difficult.\textsuperscript{73}

\textbf{One-pot Reaction.} To demonstrate the practical application of
the proposed reaction, a series of one-pot transformation sequences was
investigated (Figure 4). The C--C, C--O, C--S, C--N, and C--B
difunctionalizations of alkenes were realized through this reaction
(\textbf{6aa--6af} ). Reductive coupling (\textbf{6ag} ) and
deprotonation (\textbf{6ah} ) products were obtained after treating
\textbf{3bk} with a reductant and base, respectively.

\textbf{Figure 4.} Carbohalogenative 1,2-difunctionalization of double
bonds.

\textbf{Mechanistic Investigations.} To shed light on the reaction
mechanism, some control experiments were conducted. The reactions
of\textbf{1b} and \textbf{2k} were performed in the presence of a
radical inhibitor, 2,6-bis(1,1-dimethylethyl)-4-methylphenol (BHT). The
insertion product was obtained in 86\% yield, indicating that the
proposed reaction is unlikely to proceed \emph{via} a radical pathway
(Figure 5A). The increased yield (compared with Figure 2B) may be
explained by the inhibition of the radical polymerization of alkene by
BHT. Subsequently, a cation-exchange experiment was designed (Figure
5B), where benzhydrol was introduced as a cation donor. As expected, the
normal insertion product \textbf{3ab} was obtained in 21\% yield,
and\textbf{3bk} that was generated using benzhydrol as the benzhydryl
cation donor was obtained in 55\% yield. The formation of these products
implied that the proposed reaction proceeded through an ionic
mode.\textsuperscript{74} In addition, the intermolecular competition
between styrene \textbf{1b} and its dideuterated
analog\emph{d\textsubscript{8}}\textbf{-1b} showed a kinetic isotope
effect k\textsubscript{H}/k\textsubscript{D} = 1.00 (Figure 5C);
however, a secondary isotope effect was not observed, suggesting that
C--C and C--Cl bond formations were not involved in the rate-determining
step.\textsuperscript{75} In addition, solvent quenching experiments
were designed to elaborate the influence of the aggregated states on
such ionic insertion processes. As shown in Figure 5D, while a trace
amount (three equivalents) of commonly used solvent was introduced into
the reaction system, the desired transformation could be interrupted,
which may be ascribed to the disconnection of the aggregated state of
reactants by the solvent molecules. Notably, even nonpolar, weak
coordinating solvents such as mesitylene were competent blockers.
Possibly, there are three reasons why the solvent prevents the above
reaction. First, the cage effect of the solvent can reduce effective
collision between substrates and increase the activation energy of the
insertion process (restricted intermolecular collision, RIC). Next,
induction and coordination effects will reduce the transient effective
charge produced by the system, which is not conducive to the reaction
(charge dispersion, CD). Finally, the solvent effect may quench the
intermediates or transition states produced by the reaction, inhibiting
the reaction (intermediate quenching or transition state quenching, IQ
or TSQ). To confirm the above speculation, density functional theory
(DFT) calculations and symmetry-adapted perturbation theory (SAPT)
analysis were conducted.

\textbf{Figure 5.} Preliminary mechanistic experiments.

DFT calculations provide mechanistic insights into the abovementioned
insertion reactions of alkenes to C--X bonds. For C--Cl bond insertion
(Figure 6A), the benzyl chloride substrate \textbf{2k} heterolytically
dissociated to carbocation and chloride anion before styrene attacked
the so-generated carbocation \emph{via} a chloride anion bound
transition state (TS). Such an S\textsubscript{N}1-like reaction pathway
was exergonic (3.5 kcal/mol) with an overall free-energy barrier of 26.2
kcal/mol. Consistent with the mechanistic studies, the radical mechanism
was ruled out because the homolysis of the C--Cl bond in
\textbf{2k}seemed unfavorable as it required higher energy (by
\textgreater{}20 kcal/mol) than that in the heterolysis of the C--Cl
bond (Figure S4). Moreover, the S\textsubscript{N}2 mechanism in which a
styrene directly attacks the C(sp\textsuperscript{3}) atom of
\textbf{2k} to release a chloride anion was ruled out because it
encounters a 5 kcal/mol higher energy barrier than that in the
S\textsubscript{N}1-like mechanism.

\textbf{Figure 6.} DFT calculations and SAPT analysis.

SAPT analysis evaluates the intermolecular interaction energy between
the fragments of the obtained TS in the C--Cl bond insertion reaction
(Figure 6B). The results from this energy decomposition calculation
clearly show a strong electrostatic stabilization interaction of
\textasciitilde{}77.2 kcal/mol between the chloride anion and its
bounded benzylic counterpart. Interestingly, almost half of the
electrostatic stabilization (i.e., \textasciitilde{}35.6 kcal/mol) was
found between styrene and the remaining fragments in the TS.
Furthermore, second-order perturbation analysis based on natural bond
orbital calculations showed that a strong orbital interaction existed
between the pz orbital of the carbocation and p bonding orbital of the
olefin fragment of styrene. The calculated second-order perturbation
energy was 108.2 kcal/mol. Therefore, the temporary anchorage of the
chloride anion provided a channel for the nucleophilic attack of an
olefin and facilitated its subsequent combination with a newly generated
carbocation, providing an almost synergetic reaction mode while
suppressing the possible side reactions associated with the carbocation.
Therefore, the insertion reaction of alkenes into C--X bonds was
controlled by intrinsic factors such as strong orbital interactions and
electrostatic stabilizations between the fragments involved in the
reactions. However, if the reaction is performed under a non-aggregated
state, the abovementioned TSs or intermediates would be excluded owing
to their inevitable and much stronger interactions with solvent.

Discussion

In summary, a new strategy relying on aggregated state has enabled the
catalyst-free insertion of alkenes into C--X bonds. The
difunctionalization of alkene can be realized without using any
transition metal catalysts in the aggregated state. Practically, alkenes
were inserted into C--X (X = Cl, Br, and I) bonds \emph{via} ionic mode.
The method exhibits excellent atom and step economy and environmental
sustainability. Moreover, its practicality is highlighted by a broad
substrate scope, excellent functional-group tolerance, and extremely
simple operation. The method tolerates active functional groups such as
CHO, B(OH)\textsubscript{2}, CO\textsubscript{2}H,
Me\textsubscript{2}SiH, alkynes, and CO\textsubscript{2}Me, which are
often incompatible in transition-metal catalyzed or Lewis-acid catalyzed
reactions. This work is the first attempt to apply aggregate science to
the field of synthetic chemistry, which further expands the application
reaction of aggregation strategy as well as provides a new idea for
designing new reactions in organic chemistry.

Materials and Methods

General procedure for probing the scope of insertion of alkenes into
carbon-halogen bonds. To an oven-dried, 10 mL Te\selectlanguage{english}flon-lined screw-capped
Pyrex test tube was added aryl ethylenes (0.6 mmol) and benzyl halides
(1.8 mmol) without argon protection. A magnetic stir bar were added to
the tube carefully and the mixture was stirred slowly for 5 min at room
temperature. Then increase the temperature to 100 degC and continue to
stir for extra 5 h. After being cooled down to room temperature, it was
purified by flash chromatography on silica gel to afford pure product.
DFT calculations were performed using the ORCA program and SAPT analysis
was performed using the PSI4 code at the SAPT2+/aug-cc-pVDZ level.

Acknowledgements

This work was supported by the National Natural Science Foundation of
China (91940305, 21933009, 81874181, 22271195, 21871284), Natural
Science Foundation of Fujian Province (2021J01525), Major Scientific and
Technological Special Project for ''Significant New Drugs Creation''
(2019ZX09301158), Emerging Frontier Program of Hospital Development
Centre (SHDC12018107), Shanghai Science and Technology Development Fund
from Central Leading Local Government (YDZX20223100001004), and Shanghai
Municipal Health Commission/Shanghai Municipal Administration of
Traditional Chinese Medicine (ZY(2021-2023)-0501). The authors would
like to thank Shiyanjia Lab (www.shiyanjia.com) for the language editing
service.

Conflict of Interests

The authors declare no conflict of interests.

Supporting Information

Supporting Information is available from the Wiley Online Library or
from the author.

Received: ((will be filled in by the editorial staff)) Revised: ((will
be filled in by the editorial staff)) Published online: ((will be filled
in by the editorial staff))

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Molecular aggregation affects the electronic interactions between
molecules and has emerged as a powerful tool in material science. In
this study, aggregation strategy was applied to synthetic chemistry,
ionic insertion of alkene into carbon--halogen bond can occur smoothly
in aggregated state without any catalysts. Results show that the
non-aggregated state may quench the transition state and terminate the
insertion process.

\textbf{Keywords} aggregation enabled alkene insertion, solvent-free and
catalyst-free, atom-and step-economy

Meng-Yao Li,\textsuperscript{1,2,4} Xiao-Mei Nong,\textsuperscript{1}Han
Xiao,\textsuperscript{3} Ao Gu,\textsuperscript{1} Shuyang
Zhai,\textsuperscript{1} Jiatong Li,\textsuperscript{1} Ge
Zhang,\textsuperscript{4} Ze-Jian Xue,\textsuperscript{4} Yingbin
Liu,\textsuperscript{1*} Chunsen Li,\textsuperscript{3*} Guo-Qiang
Lin,\textsuperscript{2,4} Chen-Guo Feng\textsuperscript{2,4*}

\textbf{Title} Aggregation-enabled Alkene Insertion into Carbon--Halogen
Bonds

ToC figure

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