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\DOI{10.5802/crchim.421}
\datereceived{2025-07-15}
\daterevised{2025-09-02}
\datererevised{2025-09-03}
\dateaccepted{2025-09-08}
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\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{clarification}

\title{Exploring crystal-state vs. solution-based reactivity of
donor--acceptor cyclopropanes}

\alttitle{Comparaison de la r\'{e}activit\'{e} des cyclopropanes
donneur--accepteur en phase solide et en solution}

\author{\firstname{Michel} \lastname{Giorgi}\CDRorcid{0000-0002-4367-1985}}
\address{Aix Marseille Univ, CNRS, Centrale Med, FSCM, 13397 Marseille, France}
\email[M. Giorgi]{michel.giorgi@univ-amu.fr}

\author{\firstname{Ga\"{e}lle} \lastname{Chouraqui}\CDRorcid{0000-0003-4719-137X}\IsCorresp}
\address{Aix Marseille Univ, CNRS, Centrale Med, ISM2, 13397 Marseille, France}
\email[G. Chouraqui]{gaelle.chouraqui@univ-amu.fr}

\thanks{Agence Nationale de la Recherche (project
ANR-18-CE07-0005/Benz), French Minist\`{e}re de l'Enseignement
Sup\'{e}rieur et de la Recherche (MESR, Aix-Marseille Universit\'{e}
(AMU), Centre National de la Recherche Scientifique (CNRS),  Centrale
M\'{e}diterran\'{e}e}

\keywords{\kwd{Donor--acceptor
cyclopropane}\kwd{Rearrangement}\kwd{Topochemical
polymerization}\kwd{Benzocyclobutene}\kwd{Medium-sized ring}}

\altkeywords{\kwd{Cyclopropane
donneur--accepteur}\kwd{Transposition}\kwd{Polym\'{e}risation
topochimique}\kwd{Benzocyclobut\`{e}ne}\kwd{Cycle de taille moyenne}}

\dedicatory{This account is dedicated to my mentor, Dr. Jean-Luc
Parrain, whose intellectual integrity\break and scientific rigor have been a
source of inspiration throughout my career.}

\begin{abstract}
Donor--acceptor cyclopropanes (DACs) are highly reactive building
blocks in organic synthesis due to their combination of electronic bond
polarization and ring strain. This work explores three modes of
activation, thermal, photochemical, and catalytic, applied to the same
vinologous DAC precursor, both in solution and in the solid state.

In solution, thermal activation enables the regio- and stereoselective
formation of eight-membered carbocyclic frameworks, without the need
for catalysts or reagents, thanks to a rational precursor design based
on electronic and steric considerations. Depending on the nature of the
substituents, either a concerted or a stepwise mechanism is involved.
Additionally, and still in solution, a Lewis-acid-promoted cascade
reaction leads to benzocyclobutene scaffolds, with complete transfer of
stereochemistry into the regioselectivity of the final product.

In the solid state, exposure to X-ray radiation induces a rare
single-crystal-to-single-crystal photopolymerization, governed by
precise molecular preorganization and a degree of crystal lattice
flexibility.

Overall, this study highlights how DAC reactivity is modulated by both
the mode of activation and the physical environment, thereby offering
new strategies for the construction of complex molecules.
\end{abstract}

\begin{altabstract}
En raison de la tension de cycle et de la polarisation de leur liaison
interne, les Cyclopropanes Donneurs--Accepteurs (DACs) sont des briques
mol\'{e}culaires particuli\`{e}rement r\'{e}actives en synth\`{e}se
organique. Ce travail explore trois modes d'activation, thermique,
photochimique et catalytique, appliqu\'{e}s \`{a} un m\^{e}me
pr\'{e}curseur DAC vinylogue, aussi bien en solution qu'\`{a}
l'\'{e}tat solide.

En solution, l'activation thermique permet la formation r\'{e}gio- et
st\'{e}r\'{e}os\'{e}lective de structures carbocyliques \`{a} huit
cha\^{i}nons, sans catalyseur ni r\'{e}actif, gr\^{a}ce \`{a} une
conception rationnelle du pr\'{e}curseur fond\'{e}e sur des
consid\'{e}rations \'{e}lectroniques et st\'{e}riques. Selon la nature
des substituants, un m\'{e}canisme concert\'{e} ou en plusieurs
\'{e}tapes est mis en jeu. D'autre part, et toujours en solution, une
cascade r\'{e}actionnelle catalys\'{e}e par un acide de Lewis conduit
\`{a} des structures benzocyclobut\`{e}nes, avec un transfert total de
la st\'{e}r\'{e}ochimie vers la r\'{e}gios\'{e}lectivit\'{e} du produit
final.

\`{A} l'\'{e}tat solide, l'exposition aux rayons X induit une
photopolym\'{e}risation rare de type monocristal-\`{a}-monocristal,
r\'{e}gie par une pr\'{e}organisation mol\'{e}culaire pr\'{e}cise et
une certaine flexibilit\'{e} du r\'{e}seau cristallin.

Dans l'ensemble, cette \'{e}tude met en \'{e}vidence la mani\`{e}re
dont la r\'{e}activit\'{e} des DACs est modul\'{e}e \`{a} la fois par
le mode d'activation et par l'environnement physique, offrant ainsi de
nouvelles strat\'{e}gies pour la construction de mol\'{e}cules
complexes.
\end{altabstract}

\editornote{Article submitted by invitation}
\alteditornote{Article soumis sur invitation}

\maketitle

\twocolumngrid

\end{noXML}

\dedication{\begin{quote}\textit{This account is dedicated to my mentor, Dr. Jean-Luc
Parrain, whose intellectual integrity\break and scientific rigor have been a
source of inspiration throughout my career.}\end{quote}}

\section{Introduction}\label{sec1}

Donor--acceptor cyclopropanes (DACs) are highly versatile reactive
intermediates in organic synthesis, thanks to their unique combination
of electronic polarization and ring strain (for seminal reports on
DACs, see~\cite{1a, 1b, 1c, 1d, 1e}).  These molecules feature
electron-donating and electron-withdrawing groups on adjacent carbon
atoms, creating a pronounced \mbox{push--pull} effect that facilitates
selective bond cleavage and rearrangements. At the same time, the
significant strain inherent to the cyclopropane ring 
(${\sim}$27.5~kcal/mol) contributes a powerful driving force for a variety of
transformations. It is precisely the synergy between these two
features, electronic \mbox{polarization} and ring strain, that underpins the
distinctive reactivity of DACs (for kinetic studies on the reactivity
of DACs, see~\cite{2}).  Consequently, they have emerged as valuable
synthetic building blocks for constructing complex carbocyclic and
heterocyclic frameworks, enabling access to diverse molecular
architectures with high efficiency and selectivity (for selected
reviews on DACs chemistry, see  \cite{3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h,
3i, 3j, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3r, 3s, 3t, 3u, 3v, 3w}; for an
example on total synthesis, see~\cite{4}).

While numerous DAC-mediated transformations have been developed, the
influence of the reaction environment on their reactivity remains an
area of investigation. DAC activation can occur through thermal,
catalytic, or photochemical methods, each offering distinct benefits
and presenting specific challenges
(for different modes of activation of DACs, see~\cite{5a, 5b, 5c, 5d,
5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m}).

In solution-phase reactions, factors such as solvent polarity, thermal
input, and catalytic systems play a central role in governing
reactivity and selectivity. In contrast, crystal-state
transformations
(for seminal reports on topochemical polymerization, see 
\cite{6a, 6b, 6c, 6d}; 
for examples of topochemical polymerization, see for instance 
\cite{7a, 7b, 7c, 7d, 7e, 7f, 7g}) introduce unique considerations, including
crystal-packing effects, molecular orientation, and topochemical
restrictions, which can profoundly influence reaction
pathways~\cite{8a, 8b, 8c}. A deeper understanding of how these environmental
variables impact selectivity and product distribution is essential to
fully harness the synthetic potential of DAC chemistry. 

This account critically examines three distinct activation modes,
thermal, catalytic, and photochemical, for our in-house synthesized
DACs, studied across two different physical states (solution and
solid). Each pathway reveals unique aspects of DAC reactivity and
selectivity: thermal synthesis of eight-membered rings (solution
phase), rearrangement to benzocyclobutenes (solution phase), and
crystal-to-crystal photopolymerization (solid state). 

By comparing these three pathways, this work aims to identify key
mechanistic differences, evaluate their scope and limitations, and
illustrate how both mode of activation and reaction medium contribute
to the outcome. Ultimately, this comparative approach offers insights
into the interplay between molecular design, reaction conditions, and
functional outcomes in DAC chemistry. By bridging the gap between
solution-phase and crystal-state reactivity, this study provides
insights into how reaction environment dictates selectivity and
efficiency in DAC transformations. 

\vspace*{-2pt}

\section{Solution-phase reactivity of DACs}\label{sec2}

\vspace*{-2pt}

\subsection{Solution-phase synthesis of eight-membered rings}\label{ssec21}

\vspace*{-2pt}

This section summarizes the results recently reported by our group, in
which a thermally driven rearrangement of bis-cyclopropyl DACs afforded
eight-membered carbocyclic systems under catalyst-free conditions~\cite{9}.

Medium-sized functionalized cycles (eight- to eleven-membered rings)
occupy a unique chemical space~\cite{10a, 10b, 10c, 10d, 10e, 10f, 10g, 10h}. Their intermediate size
imparts conformational rigidity and distinct three-dimensional geometry
that can sometimes enhance biological activity by improving binding
affinity, oral bioavailability, and/or membrane permeability compared
to both acyclic analogs and rings of other sizes~\cite{11a, 11b, 11c, 11d, 11e, 11f, 11g, 10d}. Despite
these advantages, medium-sized rings remain underexplored in drug
discovery programs, largely due to well-known kinetic and thermodynamic
barriers to their synthesis. 

From a synthetic standpoint, medium-sized rings are particularly
difficult to access via classical cyclization of linear precursors,
which is often entropically disfavored. Moreover, their ring size is
small enough to experience destabilizing transannular strain. As such,
innovative synthetic strategies are required to overcome these inherent
limitations~\cite{12a, 12b, 12c, 12d, 12e}.

One promising approach involves ring-expansion reactions, particularly
starting from small strained rings like cyclopropanes~\cite{13a, 13b,
13c, 13d, 13e, 13f, 13g, 13h, 13i, 13j}. The substantial release of
ring strain (${\sim}$27.5 kcal${\cdot}$mol$^{-1}$) offers a thermodynamic
driving force, while appropriate substitution can be employed to guide
selectivity. 

\begin{scheme*}
\vspace*{2pt}
\includegraphics{sc01}
\vspace*{6pt}
\caption{\label{sch1}Design of a strategy.}
\vspace*{-2pt}
\end{scheme*}

Since divinylcyclopropanes \textbf{1} undergo Cope-type rearrangements
to form seven-membered rings \textbf{2}~\cite{14a, 14b, 14c, 14d, 14e},
and given that cyclopropanes can exhibit C--C double bond
character\footnote{In cyclopropane, the internal bond angles are forced
to be 60\textdegree, far from the ideal 109\textdegree\ angle, causing
severe angle strain. To relieve strain, the carbon atoms in
cyclopropane adjust their hybridization toward more p-character (closer
to sp$^{2}$). This gives the C--C bonds some characteristics of
${\uppi}$-bonds, similar to those in alkenes.}, we aimed to extend
this strategy by replacing one of the alkene units with a cyclopropyl
moiety (see compound \textbf{3}, Scheme~\ref{sch1}). This modification
would provide the additional carbon atom needed to access
eight-membered carbocyclic frameworks.

It is also worth noting that, for this rearrangement to occur at room
temperature or even below, a \textit{cis} relationship between the two
olefin partners is necessary (see compound \textbf{1},
Scheme~\ref{sch1})~\cite{16}. Therefore, a \textit{cis} relationship at
the C1 and C2 positions should be considered a prerequisite in the
design of precursor~\textbf{3}.

At the heart of this approach lies the donor--acceptor cyclopropane
(DAC), a class of reactive intermediates known for their versatility
(see Introduction). In our design, a \textit{gem}-ester/vinyl
ester motif was employed as the electron-withdrawing component to
promote C1--C2 bond cleavage (see compound~\textbf{5}). The donor
moiety consisted of a cyclopropyl group, whose donor reactivity has
been previously demonstrated~\cite{17a, 17b, 17c, 17d, 17e, 17f, 17g}.
To further enhance donor ability and facilitate rearrangement,
an alkoxy substituent was introduced, inspired by the known behavior of
vinyl cyclopropanols~\cite{18a, 18b, 18c, 18d, 18e},
(for reviews, see~\cite{19a, 19b}).

This design merges strain-release strategies with sigmatropic
rearrangement logic, as illustrated in Scheme~\ref{sch1}.  From a
structural perspective, the resulting precursor \textbf{5} resembles a
modified Cope system, in which one ${\uppi}$-bond is replaced by a bent
\mbox{reactive} cyclopropane~\cite{5j}. The synthesis of
biscyclopropane~\textbf{5a}, obtained in only four steps, relies on a
classical Rh(II)-mediated cyclopropanation reaction between a
vinylcyclopropane and a di-acceptor diazo derivative
(Scheme~\ref{sch2}). Notably, after three days of reflux in xylene, the
designed DAC \textbf{5a} successfully delivered the expected eight
membered ring \textbf{6a} in 83\% yield.

\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc02}
\vspace*{4pt}
\caption{\label{sch2}Proof of concept.}
\vspace*{-5pt}
\end{scheme*}

With this platform in hand, we quickly recognized that the nature of
the substituent on the donor portion of the molecule (R in
biscyclopropanes~\textbf{5}, Scheme~\ref{sch1}) significantly
influences the reaction outcome, revealing the existence of two
distinct mechanistic pathways. 

Aryl-substituted biscyclopropanes \textbf{5b--j} underwent thermal
cyclization at 100~\textdegree C to afford the corresponding
eight-membered $Z$-enol ethers~\textbf{7}, which were
subsequently hydrolyzed to ketones \textbf{6b--j} using Dowex
H$^{+}$ cation-exchange resin (Scheme~\ref{sch3}).

\begin{scheme*}
\includegraphics{sc03}
\vspace*{4pt}
\caption{\label{sch3}Exploring the aryl scope of the Cope-type
rearrangement.}
\vspace*{-8pt}
\end{scheme*}

Electron-rich, electron-poor, and \textit{ortho}-,
\mbox{\textit{meta}-,} or \textit{para}-substituted aryl groups all
participated \mbox{successfully} in the cyclization (yields ranging
from 54 to 92\%), furnishing mixtures of
\textit{cis}-/\textit{trans}-diastereomers (50:50 ${<}$ d.r.\ ${<}$ 95:5)
but consistently yielding the same ${\upbeta}$-regioisomer of ketones
\textbf{6b--j}. These results suggest that, in aryl-substituted systems
\textbf{5b--j}, the C6--C8 bond is cleaved~selectively during the
rearrangement.

In contrast, the outcome of the cyclization for alkyl-substituted
biscyclopropanes displayed a strong dependence on both the size of the
R groups (Scheme~\ref{sch1}) and the nature of the starting
\mbox{diastereomers} \textbf{5k--p} and \textbf{5n--p}$'$ (Scheme~\ref{sch4}).
In these cases, a temperature of 160~\textdegree C  was required for
the reaction to proceed. For secondary alkyl groups \textbf{5k--m} 
(R~${=}$~\textit{i}Pr, Cy), the reactions proceeded with high regio- and
diastereoselectivity (yields 70--99\%, d.r.\ {${>}$} 95:5), indicating a
preferential cleavage of the C6--C7 bond, now favoring the formation of
the ${\upalpha}$-regioisomer. In the case of smaller alkyl groups
(e.g., R ${=}$\ Me, $n$-Hex), starting from a mixture of diastereomers
\textbf{5n--p} and \textbf{5n--p}$'$, the reaction afforded mixtures of
regioisomers \textbf{6n--p} and \textbf{6n--p}$'$, while
diastereoselectivity remained excellent (yields 54--90\%; d.r.\ ${>}$
95:5, 55:45 {${<}$} $\alpha/\beta$-regioisomer ${<}$ 68:32). We showed that the
diastereomeric identity of the starting material is fully retained in
the regioisomeric outcome, i.e., each diastereomer yields a single
regioisomer.

\begin{scheme*}
\vspace*{-2pt}
\includegraphics{sc04}
\vspace*{6pt}
\caption{\label{sch4}Exploring the alkyl scope of the rearrangement.}
\vspace*{-8pt}
\end{scheme*}

These results prompted a theoretical investigation using density
functional theory (DFT) to clarify the origin of the observed
selectivity. For both methyl \textbf{6n} and \textbf{6n}$'$, and phenyl
\textbf{6b} derivatives, detailed energy profiles were established. 

Computational analysis supported a concerted but asynchronous mechanism
for both diastereomers of methyl derivatives \textbf{6n} and
\textbf{6n}$'$, initiated by the opening of the central cyclopropane ring
(Figure~\ref{fig1}). In the case of methyl derivative \textbf{6n}$'$
(Figure~\ref{fig1}, right), two atropisomers of the enol ether
(\textbf{A1} and \textbf{A2}) were identified. \textbf{A2} was found to
exist in two conformations that differed by the equatorial or axial
orientation of an ester group (see \textbf{rot}$_{\mathbf{A2-1}}$). The
\textbf{A1}/\textbf{A2} ratio depends on the reaction temperature:
\textbf{A1} was favored at 160~\textdegree C, while \textbf{A2}
predominated at 120~\textdegree C. This axial chirality arose from
restricted rotation around the C2--C3 bond. Computational data
indicated that \textbf{A2} corresponds to the kinetic product, formed
more rapidly and preferentially at lower temperature, whereas
\textbf{A1} was the thermodynamic one
(\textit{Trans}-cyclooctenes are known to \mbox{display}
atropisomerism. The transient \textit{trans}-enol ether in a 1,5- or
1,3-cyclo-octadiene has been reported before but as far as our
knowledge goes, never in the 1,4 cyclooctadiene case~\cite{20a, 20b,
20c, 20d, 20e}),  (for detailed computational studies on
(\textit{E,Z})-cycloocta-1,4-diene conformers see~\cite{21}).

\begin{figure*}
\includegraphics{fig01}
\vspace*{-2pt}
\caption{\label{fig1}Mechanistic study of the alkyl pathway.}
\vspace*{-6pt}
\end{figure*}

For phenyl derivative \textbf{6b}, the mechanism diverged. We proposed
a stepwise biradical pathway involving the ring opening of the two
\mbox{cyclopropane} moieties (Figure~\ref{fig2}, Intermediate \textbf{I}), and
low-barrier conformational changes (Figure~\ref{fig2}, intermediates
\textbf{II} and \textbf{III}) before ring closure. This pathway
\mbox{rationalized} both the observed regioselectivity and
diastereomeric mixtures.

\begin{figure*}
\includegraphics{fig02}
\vspace*{-2pt}
\caption{\label{fig2}Mechanistic study of the phenyl pathway.}
\vspace*{-2pt}
\end{figure*}

In both cases, calculations show no feasible route to the 
$E$-configured enol ethers, consistently with experimental
observations.

Through the rational design of DAC-based precursors, we have developed
a robust and {versatile} method for constructing eight-membered
carbocyclic systems under simple thermal conditions. This reaction
achieved key transformations in a \mbox{single} 
\mbox{operation:} ring opening of two
cyclopropane moieties, formation of a new C--C bond, and generation of
a medium-sized ring, all achieved in a catalyst-free, thermally driven
process.

The transformation is regio- and stereoselective, and it accommodates a
range of substituents. Two mechanistic pathways were identified, a
concerted asynchronous route and a biradical stepwise one, depending on
the electronic and steric nature of the donor part of the molecule.

This work demonstrates the powerful synergy between molecular
design, experimental validation, and computational insight, offering
new opportunities for the efficient and selective synthesis of
challenging medium-sized ring systems.

\subsection{Rearrangement of DACs to benzocyclobutenes}\label{ssec22}

As part of our ongoing investigation into the reactivity of our DAC
frameworks, we identified an unanticipated rearrangement pathway
leading to the formation of benzocyclobutene
derivatives~\cite{22}.

Benzocyclobutenes are valuable synthetic species
(for reviews on benzocyclobutenes, see~\cite{23a, 23b, 23c}), notably due
to their ability to generate {$o$-quinodimethane} ($o$QDM)
intermediates~\cite{24} {under} thermal or photochemical conditions. They
play a key role in natural product synthesis, \mbox{medicinal}
chemistry~\cite{25a, 25b, 25c, 25d, 25e, 25f, 25g, 25h, 25i}, 
and polymer/material {science~\cite{26a, 26b, 26c, 26d, 26e, 26f, 26g, 26h}.} 
While numerous synthetic methods have been reported
(for seminal reports, see~\cite{27}; 
for selected examples, see~\cite{28a, 28b, 28c, 28d, 23a, 23b, 23c}), a
general and broadly applicable approach remains challenging. We
believed that we could contribute to this effort by offering a
complementary strategy.

Remarkably, this transformation originates from the same DAC precursors
\textbf{5} that we previously employed in our annulation cascade
strategy. In the presence of a fluoride anion, a skeletal
reorganization occurred, but the product outcome differed significantly
from our initial expectations. Upon refluxing DAC precursor \textbf{5a}
(R ${=}$\ H) in THF for 16~h in the presence of a fluoride source (TBAF),
benzocyclobutene product \textbf{8a} was obtained in 58\% yield
(Scheme~\ref{sch5}). 

\begin{scheme*}
\includegraphics{sc05}
\vspace*{5pt}
\caption{\label{sch5}Rearrangement of the DAC precursor in the presence
of TBAF.}
\vspace*{-5pt}
\end{scheme*}

Mechanistically, the reaction likely begins with fluoride-mediated
deprotection of the tertiary alcohol, generating alkoxide intermediate
\textbf{B}, which could undergo a hetero-Michael addition to the
neighboring vinyl ester. Subsequent retro-Michael fragmentation of
moiety \textbf{C} could induce ring expansion to a four-membered ring
ketone \textbf{D}, reminiscent of known rearrangement of
1-silyloxy-1-vinylcyclopropanes. The resulting ketone \textbf{D} could
undergo an intramolecular aldol-type condensation to form \mbox{bicyclic}
\mbox{intermediate} \textbf{E}, followed by {elimination} and aromatization to
yield the final benzocyclobutene scaffold \textbf{8a}. Crucially, the
proposed mechanistic sequence is not purely hypothetical. Each
intermediate along this pathway was successfully isolated and fully
{characterized.} These experimental findings provide direct validation
for the stepwise mechanism.\looseness=-1

However, this fluoride-mediated protocol showed limitations. When a
substituent was present on the donor portion of DAC \textbf{5}  (R
${\neq}$ H), the reaction either stalled at the formation of
tetrahydrofuran \textbf{9k} (R ${=}$\ \textit{i}Pr; 54\% yield)
(Scheme~\ref{sch6}) or led to complete degradation of \textbf{5b} (R
${=}$\ Ph).

\begin{scheme*}
\includegraphics{sc06}
\vspace*{6pt}
\caption{\label{sch6}A very limited scope.}
\vspace*{-2pt}
\end{scheme*}

In response, we developed an alternative two-step route. Initial
exposure of the precursor \textbf{5a} to MgI$_{2}$, used as a mild
Lewis acid, rapidly (10~min only) triggered the formation of bicyclic
product \textbf{10a} by a ring-expansion/ring-opening/ring-closure
domino sequence (Scheme~\ref{sch7}). This intermediate could then
undergo a mild base-induced transetherification/elimination/aromatization
step, ultimately affording the desired benzocyclobutene
\textbf{8a} in 59\% yield~\cite{29}.

\begin{scheme*}
\includegraphics{sc07}
\vspace*{6pt}
\caption{\label{sch7}An alternative two-step route.}
\vspace*{-2pt}
\end{scheme*}

This sequence tolerated a range of substituents (R ${=}$\ primary and
secondary alkyl, aryl) and could be applied to a broader set of
substrates. As in the previous approach, regioselectivity was
controlled by the relative configuration of the starting diastereomer. 

For alkyl derivatives, each diastereoisomer led exclusively to a
distinct regioisomer. For instance, compound \textbf{5n} (R ${=}$\ Me)
underwent C6--C7 cleavage to furnish regioisomer \textbf{8a} (R ${=}$\
Me),  while its diastereomer \textbf{5n}$'$ (R ${=}$\ Me) followed an
alternate bond \mbox{reorganization} route (C6--C8 bond cleavage), yielding
regioisomer \textbf{8a}$'$ (R ${=}$\ Me) (Scheme~\ref{sch8}).  This strict
correspondence between initial stereochemistry and final regioisomer
demonstrates a complete transfer of diastereoselectivity into
regioselectivity, offering rare predictive control over the product
distribution.

\begin{scheme*}
\includegraphics{sc08}
\vspace*{6pt}
\caption{\label{sch8}Alkyl derivatives---total transfer of
diastereoselectivity into the regioselectivity.}
\vspace*{-2pt}
\end{scheme*}

The nature of the substituent profoundly impacted the regioselectivity
of the DAC ring opening. Aryl-substituted analogs consistently favored
C6--C8 cleavage (Scheme~\ref{sch9}). 

\begin{scheme*}
\includegraphics{sc09}
\vspace*{6pt}
\caption{\label{sch9}Aryl derivatives---the opposite regioisomer.}
\vspace*{-2pt}
\end{scheme*}

These divergent behaviors echo isolated reports in related cyclopropyl
ether systems~\cite{30,9} and also other cyclizations~\cite{31}. A
concerted mechanism likely governs the alkyl series, minimizing steric
repulsion in the transition state, whereas the aryl series appears to
favor a stepwise pathway, enabled by stabilization of a benzyl
carbocation intermediate. These findings demonstrate how fine-tuning
the electronic profile of DACs can serve as a powerful tool to control
reactivity and regioselectivity across mechanistically distinct
pathways.

The elegance of this approach lies in its conciseness, a two-step
sequence encompassing six elementary transformations, all initiated
from a simple yet functionally rich cyclopropane framework. The method
offers a direct and efficient route to benzocyclobutene scaffolds, with
complete regio- and diastereocontrol, and compatible with a range of
functional groups.

Taken together, these results not only unveil a new facet of DAC
reactivity but also underscore the power of combining ring strain,
stereoelectronic \mbox{effects,} and tailored reaction conditions to access
otherwise challenging molecular architectures.

\section{Solid-state photopolymerization of donor--acceptor
cyclopropanes}\label{sec3}

{\advance\baselineskip by -.1pt

In our recent investigations of DACs, we identified an unexpected
reactivity pathway occurring in the solid state, distinct from the
thermal behavior observed in solution. While characterizing vinyl
bis-cyclopropane compound \textbf{6a} (R$^{1}=p$-F) by single-crystal
X-ray diffraction (SCXRD), we unexpectedly found that even a short
exposure (10 min) to Cu radiation triggered a notable transformation of
the crystal packing, leading to the emergence of a layered structure
composed of both intact monomers and newly generated polymer chains
(Scheme~\ref{sch10}, left side)~\cite{32}. Structural analysis
indicated that polymerization proceeded via ring opening of both
cyclopropane units, leading to covalent linkage between benzylic (C8)
and vinyl carbons (C14) of adjacent monomers. The resulting polymeric
chain \textbf{10} (Scheme~\ref{sch10}, right side) displayed two
non-conjugated $Z$-alkenes and two stereocenters per repeating unit,
features difficult to access via conventional solution-phase methods.

\begin{scheme*}
\includegraphics{sc10}
\vspace*{4pt}
\caption{\label{sch10}Topochemical polymerization.}
\vspace*{-8pt}
\end{scheme*}

To gain structural insight into the pre-reactive state of the crystal,
we performed SCXRD analysis at 150~K, a temperature deliberately chosen
to lie below the reaction threshold. Under these conditions, the system
remains unreactive, allowing direct observation of the intact monomer.
The structure revealed the presence of two closely related conformers,
$\mathbi{p}$\textbf{-F-m} and $\mathbi{p}$\textbf{-F-p}, coexisting in
the asymmetric unit (Scheme~\ref{sch11}). These conformers were nearly
superimposable, differing primarily by an approximate 65\textdegree\
rotation around the terminal ethyl group of the vinyl ester
(Scheme~\ref{sch11}, right side). Notably, only the
$\mathbi{p}$\textbf{-F-p} conformer adopted a spatial arrangement
favorable for topochemical polymerization, with a distance of
4.324~\AA{} between the reactive carbons C8 and C14i, allowing
head-to-tail propagation along a crystallographic axis
(Schmidt's rules say a distance ${<}$ 4.2~\AA{} is needed between reactive
site for a topochemical reaction to occur~\cite{32a} and see reference 
\cite{6c} but this can be overcome if there is enough
void space in the crystal to allow molecular movement~\cite{33a, 33b}).
Due to the centrosymmetric packing of the crystal, polymer growth
proceeds in a racemic fashion. This structural snapshot illustrates how
small conformational variations and crystal symmetry elements govern
the selectivity and outcome of solid-state transformations.

}

\begin{scheme*}
\includegraphics{sc11}
\vspace*{5pt}
\caption{\label{sch11}Initial crystal packing of the monomer.}
\vspace*{-6pt}
\end{scheme*}

To explore the generality of the observed solid-state reactivity, we
extended our study to a broader set of DAC derivatives. Among the
compounds tested, only the \textit{para}-chlorobenzene
$\mathbi{p}$\textbf{-Cl} and \textit{meta}-fluorobenzene
$\mathbi{m}$\textbf{-F} analogs exhibited molecular arrangements
compatible with topochemical reactivity. Measurements by SCXRD
performed at 150~K revealed that each of these derivatives crystallized
with a single conformer per asymmetric unit.

The $\mathbi{p}$\textbf{-Cl} derivative underwent a
temperature-dependent transformation that could be resolved into a
series of well-defined intermediate states, ultimately leading to a
topochemical polymerization. Upon warming to 250~K, two partially
reacted species were detected in a 2:1 occupancy ratio. In the dominant
species, the inner C--C bond of one cyclopropane stretched to 
1.713(9)~\AA{}. In the minor species, full ring opening of the second
cyclopropane was observed. This transformation progressed further at
270~K, with the reactive bond reaching 1.87(1) \AA{}. These structural
snapshots suggest a possible manifestation of push--pull polarization,
as evidenced by progressive bond elongation prior to full cleavage.
While this behavior aligns with expectations for DAC systems, it must
be interpreted cautiously, since crystallographic data alone do not
offer direct insight into electronic structure~\cite{34}. By 290~K, the
crystals did not diffract anymore, reflecting the loss of crystalline
integrity. In contrast, the $\mathbi{m}$\textbf{-F} analog, despite its
favorable preorganization, showed no signs of reactivity at any
measurement temperature. 

Molecular dynamics (MD) simulations revealed that favorable alignment
of reactive centers must be coupled with sufficient molecular motion to
allow bond reorganization. For $\mathbi{p}$\textbf{-F}, such motions,
especially perpendicular to the polymerization axis, were accommodated
without compromising lattice coherence. In the case of
$\mathbi{p}$\textbf{-Cl}, movement was largely restricted to the
direction of polymerization, resulting in mechanical stress and~crystal
collapse during the polymer growth. Despite its favorable packing and
geometric preorganization, $\mathbi{m}$\textbf{-F} remained unreactive.
This lack of reactivity can be attributed to an insufficient number of
internal degrees of freedom. There was not enough conformational
\mbox{flexibility} to accommodate the structural rearrangements required for
polymerization. Interestingly, the non-reactive conformers in
$\mathbi{p}$\textbf{-F} played a stabilizing role, possibly acting as
\mbox{molecular}
\mbox{templates~\cite{35a, 35b}.} This divergence underscored the
importance of not only geometric alignment, but also conformational
flexibility and packing plasticity in enabling productive reactivity.

Collectively, these observations demonstrated that the~crystalline
environment acts as a true reaction variable, comparable to classical
parameters such as temperature or pressure. It not only \mbox{influences}
reaction rates, but also determines mechanistic pathways and enables
access to product architectures that remain elusive in
solution~\cite{36a, 36b, 36c, 36d, 36e, 8a, 8b}. The topochemical constraints observed in DAC
systems reveal a distinctive mode of reactivity, intimately tied to
molecular packing and conformational freedom.

The combined use of SCXRD and molecular dynamics simulations~\cite{37a,
37b, 37c}\footnote{To the best of our knowledge, molecular dynamics
(MD) has rarely been used to study crystal-to-crystal transformations
in organic  systems.}
provided an atomically resolved view of this rare
single-crystal-to-single-crystal polymerization. This approach allowed
us to capture the interplay between molecular orientation, symmetry,
and lattice plasticity with unprecedented clarity. Although predicting
whether a given reaction will proceed in the solid state remains
challenging, the introduction of ring strain and, more broadly, of
built-in structural tension that seeks release, emerges as a promising
strategy to bias systems toward reactivity under topochemical\break
constraints.

\section{Critical discussion}\label{sec4}

Beyond their distinct activation conditions, the contrasting reactivity
profiles of donor--acceptor cyclopropanes (DACs) in solution and in the
solid state emphasize the structural versatility and mechanistic
richness in this class of compounds. In solution, DACs undergo cascade
transformations such as ring expansion, rearrangement, and
condensation, typically under mild thermal or basic conditions and
often without the need for additional catalysts. These processes are
largely governed by the intrinsic electronic polarization of the
substrate and, critically, by the release of ring strain embedded in
the cyclopropane core. This strain allows complex bond reorganizations
to occur efficiently and selectively.

In the solid state, DACs display a fundamentally different mode of
reactivity. The transformation is constrained by crystal packing,
requiring precise \mbox{preorganization} of reactive units and sufficient
lattice flexibility. Under these topochemical conditions,
polymerization or bond cleavage occurs only when the spatial
arrangement is favorable. Yet here too, ring strain plays a central
role---facilitating the reaction by providing a thermodynamic incentive
for bond rupture, even in the absence of molecular mobility. Although
predicting whether a given \mbox{transformation} will proceed in the solid
state remains inherently challenging, the deliberate incorporation of
strain---and more generally, of structural tension that seeks
release---emerges as a rational design element to bias systems toward
productive\break reactivity.

However, a key limitation of this approach lies in its lack of
scalability. To date, the solid-state transformations that we observe
remain confined to single-crystal-to-single-crystal conversions, which
require highly ordered materials and low-throughput handling. We have
not yet identified operationally simple or bench-stable conditions that
would enable these reactions to be performed in batch or on preparative
scale. As such, while mechanistically instructive and structurally
unique, the synthetic utility of these transformations is currently
constrained by practical considerations.

Importantly, the reactivity principles traditionally associated with
vinyl-cyclopropanol derivatives---well-known for undergoing ring
opening and rearrangement---can be effectively transposed to
biscyclopropanol systems. These more complex frameworks preserve the
electronic and conformational features of their monosubstituted analogs
but introduce new degrees of freedom and stereochemical control. In
this context, the complete transfer of stereochemical information into
regioselectivity, where each diastereomer leads unambiguously to a
specific regioisomer, highlights the importance of geometric
predisposition in steering divergent mechanistic pathways. This
observation underscores how subtle differences in molecular orientation
in strained systems can dictate not only product identity but also
reaction trajectory.

Together, these insights consolidate DACs as uniquely powerful
platforms for controlling molecular reorganization across environments.
Whether in solution or in the solid state, they provide rare access to
structurally complex, stereochemically defined products through
mechanistically distinct yet conceptually unified strategies.

\section{Conclusion and future directions}\label{sec5}

Taken together, these studies emphasize the synthetic potential of
donor--acceptor cyclopropanes as highly versatile platforms for
molecular construction. Whether activated in solution through
well-orchestrated domino sequences or engaged in solid-state
transformations dictated by lattice constraints, DACs enable access to
diverse and \mbox{otherwise} \mbox{challenging} structural motifs. The capacity to
translate reactivity patterns, such as ring expansion or rearrangement,
from simpler vinyl-cyclopropanol systems to more elaborate
bis-cyclopropane derivatives, further highlights the adaptability of
this class of compounds. Beyond their synthetic utility, these
transformations offer rare mechanistic insights into the interplay
between strain release, stereoelectronic effects, and medium-dependent
selectivity. This duality of behavior not only broadens the scope of
DAC chemistry but also opens new avenues for rational design of
reactivity, both in and beyond conventional solution-phase settings.

\section*{Acknowledgments}

I would like to express my gratitude
to my coworkers and collaborators who participated in this project: 
Dr.~Bohdan Biletskyi, Dr.~Sara Chentouf, Dr.~Pierre Colonna, Professor
Laurent Commeiras, Dr.~Maxime Dousset, Dr.~Virginie H\'{e}ran, 
Dr.~K\'{e}vin Masson, Dr.~Jean-Val\`{e}re Naubron, Dr.~Paola Nava and 
Dr.~Fabio Ziarelli. This work was supported by the computing facilities
of the ``Centre R\'egional de Comp\'etences en Mod\'elisation
Mol\'eculaire de Marseille'' (CRCMM).

\section*{Declaration of interests}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.

\section*{Funding}

We gratefully acknowledge the Agence Nationale de la Recherche (project
ANR-18-CE07-0005/Benz) for its financial support. We thank the French
Minist\`{e}re de l'Enseignement Sup\'{e}rieur et de la Recherche (MESR)
for PhD fellowships. We also acknowledge institutional financial
support from Aix-Marseille Universit\'{e} (AMU), the Centre National de
la Recherche Scientifique (CNRS), and Centrale M\'{e}diterran\'{e}e.

\CDRGrant[ANR]{ANR-18-CE07-0005/Benz}

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