Substituent Effects in Mechanochemical Allowed and Forbidden Cyclobutene Ring-Opening Reactions

Article abstract of DOI:10.1021/jacs.0c12088

Woodward and Hoffman once jested that a very powerful Maxwell demon could seize a molecule of cyclobutene at its methylene groups and tear it open in a disrotatory fashion to obtain butadiene (Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry. Angew. Chem., Int. Ed. 1969, 8, 781-853). Nearly 40 years later, that demon was discovered, and the field of covalent polymer mechanochemistry was born. In the decade since our demon was befriended, many fundamental investigations have been undertaken to build up our understanding of force-modified pathways for electrocyclic ring-opening reactions. Here, we seek to extend that fundamental understanding by exploring substituent effects in allowed and forbidden ring-opening reactions of cyclobutene (CBE) and benzocyclobutene (BCB) using a combination of single-molecule force spectroscopy (SMFS) and computation. We show that, while the forbidden ring-opening of cis-BCB occurs at a lower force than the allowed ring-opening of trans-BCB on the time scale of the SMFS experiment, the opposite is true for cis- and trans-CBE. Such a reactivity flip is explained through computational analysis and discussion of the so-called allowed/forbidden gap.

Full text of DOI:10.1021/jacs.0c12088

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Article
Substituent Effects in Mechanochemical Allowed and Forbidden
Cyclobutene Ring-Opening Reactions
Cameron L. Brown, Brandon H. Bowser, Jan Meisner, Tatiana B. Kouznetsova, Stefan Seritan,
Todd J. Martinez,* and Stephen L. Craig*
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ABSTRACT: Woodward and Hoffman once jested that a very powerful Maxwell demon could seize a molecule of cyclobutene at its
methylene groups and tear it open in a disrotatory fashion to obtain butadiene (Woodward, R. B.; Hoffmann, R. The Conservation
of Orbital Symmetry. Angew. Chem., Int. Ed. 1969, 8, 781−853). Nearly 40 years later, that demon was discovered, and the field of
covalent polymer mechanochemistry was born. In the decade since our demon was befriended, many fundamental investigations
have been undertaken to build up our understanding of force-modified pathways for electrocyclic ring-opening reactions. Here, we
seek to extend that fundamental understanding by exploring substituent effects in allowed and forbidden ring-opening reactions of
cyclobutene (CBE) and benzocyclobutene (BCB) using a combination of single-molecule force spectroscopy (SMFS) and
computation. We show that, while the forbidden ring-opening of cis-BCB occurs at a lower force than the allowed ring-opening of
trans-BCB on the time scale of the SMFS experiment, the opposite is true for cis- and trans-CBE. Such a reactivity flip is explained
through computational analysis and discussion of the so-called allowed/forbidden gap.
have higher energy barriers to conrotatory ring-opening than
do CBEs.1,13−16
INTRODUCTION
■
Electrocyclic reactions have wide utility in both organic
synthesis and as the basis for understanding fundamental
aspects of chemical reactivity,1,2 in particular those related to
the role of orbital symmetry and concepts of frontier molecular
orbital theory. The influence of substituents on electronic
structure and reactivity has therefore received much attention.
For example, in the paradigmatic conrotatory 4 π-electron ring-
opening of cyclobutene (CBE) to 1,3-butadiene, substituents
on the ring play a key role in determining thermal barriers to
ring-opening,1,3−9 the torque selectivity of the ring-open-
ing,10−12 and the subsequent reactivity of the ring-opened
products.13 Substituents attached to the breaking σ bond have
been shown to perturb the activation energy of the conrotatory
ring-opening by as much as 7 kcal/mol per substituent.14 In
general, electron donors weaken the adjacent σ bond and
promote outward rotation, whereas strong acceptors favor
inward rotation.9 Substituents attached to the double bond of
the cyclobutene ring, on the other hand, typically have a
smaller effect (∼1−3 kcal/mol) on the barrier to conrotatory
ring-opening of CBE.9 A notable exception is found in
benzocyclobutene (BCB), in which case the nascent double
bond is also part of an aromatic framework. In general, the
CBE ring-opened butadiene product is more stable than the
CBE reactant; however, the opposite is true for BCB due to the
resulting loss of aromaticity.15 Additionally, BCBs typically
Whereas substituent effects have been well documented in
the thermally allowed conrotatory ring-opening of CBEs and
BCBs,1,7,8,12 a much smaller set of studies have probed the
thermally forbidden disrotatory ring-opening reaction, even in
parent reactions.16−19 The relative dearth of studies is due to
the high stereospecificity associated with the conrotatory ring-
opening reaction, which makes violations of the so-called
Woodward−Hoffmann rules1 exceedingly rare. A seminal
experimental study by Brauman et al. on the allowed/
forbidden gap (ΔGA/F), that is, the difference in the activation
energies of the symmetry forbidden (disrotatory) and
symmetry allowed (conrotatory) reaction, places ΔGA/F at
greater than 15 kcal/mol for a dimethyl-substituted CBE.20
Lee et al. later showed that ΔGA/F can be altered by
introducing planarity constraints on the CBE ring, which
decreases favorable orbital interaction between both the σ and
π* orbitals and the π and σ* orbitals in the conrotatory
Received: November 18, 2020
Published: March 5, 2021
https://dx.doi.org/10.1021/jacs.0c12088
J. Am. Chem. Soc. 2021, 143, 3846−3855
© 2021 American Chemical Society
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Figure 1. Top: Summary of computational findings from Sakai that compare the allowed−forbidden energy gap for the thermal ring-opening
reaction of CBE and BCB.17,18 Bottom: Summary of key mechanophores and processes that were studied by both SMFS and computational
modeling and reported here.
transition state.16 Sakai calculated that the symmetry forbidden
disrotatory ring-openings of both CBE17 and BCB18 proceed
through a diradical mechanism, and the calculated ΔGA/F for
BCB (∼8 kcal/mol) is found to be 11 kcal/mol lower than the
ΔGA/F for CBE (∼19 kcal/mol), according to computations at
the CAS-MP2/6-31G(d,p) level of theory (Figure 1).18 The
calculated transition state structures indicate that a lower
ΔGA/F is a result of the disrotatory pathway in BCB retaining
aromatic character that is lost at the transition state of the
conrotatory pathways. These calculations that directly compare
the allowed and forbidden ring-opening pathways for CBE and
BCB have yet to be verified experimentally, primarily because
the high barriers to classically forbidden reactions limit the
toolkit available for their study. Herein, we employ covalent
polymer mechanochemistry to probe forbidden reactivity and
compare experimental reactivities to the computational results
(Figure 1).
Over the past decade, advances in covalent polymer
mechanochemistry have provided a motivation for better
understanding symmetry forbidden processes, as well as tools
and methods by which that understanding can be obtained.
The motivation comes from the fact that coupled mechanical
forces can be used to steer electrocyclic reactions down
pathways that are opposite to the Woodward−Hoffmann
(WH) rules, leading to opportunities in both stress-responsive
materials and new chemical reaction manifolds. Moore and co-
workers demonstrated that high forces of tension applied to cis-
diester attachments on BCB force the reaction mechanism to
change from a symmetry allowed thermal conrotatory pathway
to a symmetry forbidden thermal disrotatory pathway.21 This
groundbreaking study has been followed by computation-
al22−29 and experimental30−33 work aimed at developing a
better fundamental understanding of the mechanochemically
accelerated reactions of CBE and BCB, and numerous
additional examples of analogous apparent violations of orbital
symmetry rules have been reported in other systems.34 At the
same time, mechanochemical coupling has provided a means
of exploring symmetry forbidden reactivity manifolds that have
otherwise remained hidden. For example, Wang et al. used
single-molecule force spectroscopy (SMFS) experiments to
quantify the force-coupled reactivity of a dialkyl-substituted
BCB. The force necessary to accelerate the rate constant of the
disrotatory ring-opening reaction of cis-BCB to ∼10 s−1 is
lower than that required to achieve the same rate in the
conrotatory ring-opening reaction of its trans-BCB analogue
(1a).32 They found that the crossover force at which cis-BCB
undergoes a disrotatory ring-opening faster than trans-BCB
undergoes a conrotatory ring-opening is less than 1370 pN,
which is lower than that predicted for a dimethyl-substituted
BCB system (∼1600 pN).24
By further applying the SMFS technique, here we system-
atically explore the differences in both the allowed (con-
rotatory) and the forbidden (disrotatory) reactivity of the CBE
and BCB mechanophore systems. We first performed SMFS
experiments on the trans-CBE and trans-BCB mechanophores
to probe differences in the allowed pathway, in which electron
density shifts in a fully synchronous manner (blue, Figure 1).
Second, we performed SMFS experiments on the cis-CBE and
cis-BCB mechanophores to probe differences between the
forbidden pathways, in which, according to the work of
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Sakai,17,18 the electron density shifts asynchronously and there
is a buildup of diradical character (red, Figure 1). Third, we
explore the differences between the allowed and forbidden
processes for both CBE and BCB, to gain experimental insights
into structure−activity relationships that influence ΔGA/F in 4
π-electron ring-opening reactions. The experimental results are
supported by computational studies of the ring-opening
reactions using the force-modified potential energy surface
(FMPES) approach.22 The FMPES approach provides
activation barriers for ring-opening as a function of force that
can be directly compared to the SMFS results. The underlying
electronic structure of the force-free and force-coupled
reactions is further explored using CASSCF/6-31G* calcu-
lations at 0 and 2 nN, respectively. In particular, these
calculations provide insight into the degree of synchronicity
and diradicaloid character of the allowed and forbidden
processes and identify correlations between electronic
structure and differences in CBE and BCB reactivity. Finally,
we evaluate the effects of pulling attachments on the allowed
and forbidden reactivity, and in particular the force-coupled
allowed−forbidden gap, of the BCB mechanophore by
comparing SMFS and computational data for diester-BCB to
the aforementioned dialkyl-BCB.
plotted using homemade software written in Matlab language. To
obtain the relative extension at the plateaus, the contour lengths of the
polymers before and after transition were determined by fitting the
pre- and post-transition force curves to an extended freely jointed
chain (FJC) model as described previously.37,38 Such a fit allows the
determination of polymer chain lengths corresponding to the initial
state, when active mechanophores are intact (L1), and the final state,
when all mechanophores have undergone an irreversible ring-opening
reaction (L2).
Experimentally determined values of L1 and L2 are compared to
modeled values of the contour lengths of the repeating units by a
method described previously.37 The equilibrium conformers of the
molecules were minimized at the Molecular Mechanics/MMFF level
of theory using Spartan software.37 The end-to-end distance of the
molecule was constrained until the bonding geometries were
noticeably distorted. CoGEF (constrained geometry simulates
external force)41,42 plots of energy versus displacement were then
obtained by varying the constraint in 0.1 Å increments. The
incremental change in energy versus change in distance was taken
as the force at the midpoint of the increment, and the resulting force
versus displacement curve was extrapolated to zero force to give a
force-free contour length (LRC or LRO) of the computational polymer
fragment where RC and RO stand for ring-closed and ring-opened,
respectively. Lepoxy COD was determined previously to be 9.30 Å.32 The
ratio of polymer contour lengths, L2/L1, was obtained from the
following equation:
METHODS
■
Synthesis of Multimechanophore-Containing Copolymers.
Multimechanophore polymers bearing the CBE and BCB units of
interest were generated using a tandem ring-closing/ring-opening
strategy reported previously (Figure 2).35 The ring-closing metathesis
(LRO × χRO) + (Lepoxy COD × χ
(LRC × χRC) + (Lepoxy COD × χ
)
)
L2
L1
epoxy COD
=
epoxy COD
where χ denotes the mole fraction of a particular repeating unit (as
1
determined by H NMR spectroscopy), and L refers to the end-to-
end distance obtained from CoGEF calculations for the correspond-
ing repeat.
Computational Modeling. Free energy barriers were calculated
using force-modified potential energy surfaces (FMPES).22 The
B3LYP density functional and the 6-31G* basis set were used and
compared to wave function-based methods;43−47 see the Supporting
Information for further information. We demonstrate the influence of
solvation to be negligible (see the Supporting Information) due to the
unipolar nature of toluene; therefore, all calculations are performed in
the gas phase. Forces were applied to the outermost carbon atoms of
the model mechanophores. In previous studies, this model has proven
to be effective in assessing the mechanochemical reactivity of
mechanophores embedded within polymers.26,48 For the conrotatory
ring-opening of trans-substituted CBEs and BCBs, reactants and
transition structures are optimized on the force-free PES and on
FMPES in steps of 0.5 nN. At forces above a critical value (4.0 nN for
trans-BCB, 3.0 nN for cis-BCBs, and 3.5 nN for cis- and trans-CBEs),
the reactants have no stable minimum structures on the respective
FMPES; in other words, immediate (barrierless) ring-opening would
occur at these forces. For the disrotatory ring-opening of cis-
substituted CBEs and BCBs, transition state optimization below 0.5
nN (1.0 nN for CBE) converged to the conrotatory transition
structure, indicating that there is no first-order saddle point associated
with this reaction channel.16 For the conrotatory ring-opening of cis-
substituted CBEs and BCBs, transition states have been optimized
below a system-dependent critical force at which the first-order saddle
point associated with this reaction channel disappears.23,24 At these
threshold forces (>0.5 nN for alkyl-BCB, >1.0 nN for ester-BCB, and
>2.5 nN for CBE), the topology of the FMPES changes significantly,
which will be the subject of future computational studies.
Figure 2. (a) Cartoon of the RCM−ROMP synthetic approach. (b)
Copolymers used in this study, generated from RCM−ROMP.
(RCM) of bis-alkene-functionalized CBE/BCB mechanophores
yielded mechanophore-containing macrocycles. The CBE and BCB
macrocycles were then copolymerized with freshly distilled 9-
oxabicyclo[6.1.0]non-4-ene (epoxy-COD)36 via ring-opening meta-
thesis polymerization (ROMP) to give multimechanophore-contain-
ing polymers P1a, P1b, P2a, and P2b. Mechanically inert epoxides
were incorporated to increase the adhesion force between the polymer
and the tip of the atomic force microscope (AFM) cantilever.37
Copolymers containing either both cis- and trans-CBE isomers (P1c,
see the Supporting Information) or both cis- and trans-BCB isomers
(P2c, see the Supporting Information) were also synthesized.
Single-Molecule Force Spectroscopy. The SMFS pulling
experiments were conducted in toluene at ambient temperature
(∼23 °C) in the same manner as described previously,32,37−39 using a
homemade AFM, which was constructed using a Digital Instruments
scanning head mounted on top of a piezoelectric positioner, similar to
that described in detail previously.40 Force curves were collected in
dSPACE (dSPACE Inc., Wixom, MI) and analyzed using Matlab
(The MathWorks, Inc., Natick, MA). All data were filtered during
acquisition at 500 Hz. After acquisition, the data were calibrated and
For the calculation of the natural orbitals along the reaction
pathways, complete-active-space self-consistent field (CASSCF)
calculations have been performed (see the Supporting Information
for further information). The effective number of unpaired electrons
(ENUE) is calculated according to
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Figure 3. Overlay of several force versus separation curves for copolymers P1a (a) and P2a (b). The curves were normalized to have the same
separation at a force of 500 pN. The reported f* is an average of several curves and was determined according to the process described in the
■
●
Methods. (c) Activation barriers as a function of force for both trans-CBE ( ) and trans-BCB ( ) mechanophores, calculated as described in the
Methods. The dotted line represents the activation barrier for a generic chemical reaction that has a rate constant of 10 s−1 at 298 K, which is a
reasonable approximation for the rate of ring-opening of the mechanophores during SMFS experiments.
Table 1. Plateau Force Corresponding to Mechanochemical CBE/BCB Ring-Opening (f*), Calculated Conrotatory (con) and
Disrotatory (dis) Ring-Opening Activation Energies (ΔG⧧) at F = 0 nN and F = 2 nN, Percent of Polymer Repeating Units
Containing Either CBE or BCB, the Ratio of Polymer Contour Length before and after Mechanochemical Activation (L2/L1)
by Fitting with a Freely Jointed Chain Model (FJC), and Theoretical L2/L1 Ratios by Modeling if All Ring-Opened Products
Are the E,E-Isomer and if All Ring-Opened Products Are the E,Z-Isomer
polymer
f* (pN)
ΔG⧧F=0(con)
ΔG⧧F=2(con)
ΔG⧧F=2(dis)
%CBE or BCB
L2/L1 (FJC)
L2/L1 (model-E,E)
L2/L1 (model-E,Z)
P1a
P1b
P2a
P2b
1270
1520
1490
1040
25.7
31.7
29.9
38.7
8.7
21%
18%
29%
22%
1.07
1.08
1.05
1.05
1.05
1.05
1.05
1.05
1.03
1.04
1.02
1.03
10.1
3.9
12.8
m
1
determined by H NMR to be 21% and 29%, respectively.
According to CoGEF calculations,41,42 P1a is expected to
undergo approximately a 5% elongation if the E,E-isomer is the
sole ring-opened product and approximately a 3% elongation if
the E,Z-isomer is the sole ring-opened product. Similarly, P2a
is expected to undergo approximately a 5% elongation (E,E-
isomer) and a 2% elongation (E,Z-isomer). The average
observed elongations by SMFS for P1a and P2a (7% and 5%,
respectively) are thus more consistent with the mechanically
generated E,E-ring-opened product expected from the “WH-
allowed”, conrotatory ring-opening (see the Supporting
Information for details).
N =
n2(2 − n )2
∑
i
i
i=1
where ni is the natural orbital occupation number of the active orbital
i.49 Closed and unoccupied (virtual) orbitals do not contribute to the
ENUE.
RESULTS AND DISCUSSION
■
Woodward−Hoffmann Allowed trans-Pulling. Figure
3a,b shows experimental force versus separation curves for
polymers P1a and P2a, containing trans-CBE and trans-BCB
mechanophores, respectively. Each plateau can be charac-
terized by a single force, f*, determined by taking the second
derivative of the force−separation curve and finding the
inflection point. The plateau and its corresponding f* reflect
the force required to mechanically accelerate the half-life of the
CBE and BCB ring-opening reactions to approximately ∼100
ms, and values of f* are consistent across all of the pulls of a
given type of polymer gathered over several days and multiple
cantilevers. In this way, f* was determined to be 1270 and
1490 pN for polymers P1a and P2a, respectively (Table 1).
The mechanically induced plateaus can be further charac-
terized by the ratio L2/L1, where L2 is the polymer contour
length after mechanical activation and L1 is the polymer
contour length before mechanical activation. This ratio is a
function of the change in contour length of each
mechanophore repeat and the relative ratio of mechanophore
to epoxy-COD repeat. By pulling on a trans-substituted CBE
or BCB mechanophore, the mechanical work is directly
coupled to the thermally allowed conrotatory ring-opening
pathway, and thus the E,E-ring-opened products are expected.
The trans-CBE-containing copolymer (P1a) and trans-BCB-
containing copolymer (P2a) were synthesized as described
above, and the percent incorporation of mechanophore was
Figure 3c shows plots of computationally determined B3LYP
FMPES activation energies (ΔG⧧) as a function of applied
force for trans-substituted CBE and BCB mechanophores.
Initially, the force-free ΔG⧧con of trans-CBE (25.7 kcal/mol) is
∼4 kcal/mol lower than that of trans-BCB (29.9 kcal/mol). In
general, BCB ring systems tend to be less thermally reactive
than analogous CBE ring systems due to the loss of aromaticity
in the o-QDM products, which slows the ring-opening of
BCB.16,18 As the applied mechanical force via the trans-
attachments increases, ΔG⧧ decreases at relatively the same
con
rate in both cases, and the energy gap between them does not
change significantly until higher forces are experienced (>3.0
nN). This suggests that the mechanical coupling is similar for
both systems at the forces that correspond to reactivity on the
time scale of the SMFS experiment.
The point where the curve intersects the black dotted line in
Figure 3c represents the force at which the activation barrier is
lowered to ∼16.6 kcal/mol, which corresponds to a rate
constant for ring-opening that would lead to a typical plateau
extension in the SMFS experiments (∼10 s−1). This force
therefore reflects the value of f* expected solely on the basis of
the FMPES computations. Figure 3c indicates that this
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Figure 4. Overlay of several force versus separation curves for copolymers P1b (a) and P2b (b). The curves were normalized to have the same
separation at a force of 500 pN. The reported f* is an average of several curves and was determined according to the process described in the
■
●
Methods. (c) Activation barriers as a function of force for both cis-CBE ( ) and cis-BCB ( ) mechanophores, calculated as described in the
Methods. The dotted line represents the activation barrier for a generic chemical reaction that has a rate constant of 10 s−1 at 298 K, which is a
reasonable approximation for the rate of ring-opening of the mechanophores during SMFS experiments.
calculated force is lower for the trans-CBE mechanophore
(1.10 nN) than that of the trans-BCB mechanophore (1.60
nN), and these computational results are qualitatively
consistent with our experimental SMFS results for P1a and
P2a. Because the rates at which the activation barriers change
as a function of force are similar (below 3 nN), these observed
differences in force-coupled reactivity are primarily attributed
to differences in the intrinsic ring-opening reactivity of CBE
and BCB, as opposed to differences in the mechanical
coupling.
Woodward−Hoffmann Forbidden cis-Pulling. Figure
4a,b shows experimental force versus separation curves for P1b
and P2b, containing cis-CBE and cis-BCB mechanophores,
respectively. Using the same approach as in the trans-
substituted case, f* was determined to be 1520 pN for P1b
and 1040 pN for P2b (Table 1). These experimental
observations correspond well to the values of 1.54 and 1.04
nN, respectively, expected on the basis of FMPES calculations
(Figure 4c). In contrast to the trans-substituted mechano-
phores, where the thermally allowed conrotatory reaction was
mechanically induced, early work on stretching cis-substituted
CBE or BCB mechanophores has shown that mechanical work
can directly couple to the thermally forbidden disrotatory ring-
opening pathway to give the E,E-ring-opened products.21−24
Recently, however, Tian et al. have reported that for (Z)-2,3-
diphenylcyclobutene-1,4-dicarboxylate, low forces also me-
chanically accelerate the conrotatory reaction, and a mixture of
E,E and E,Z products was observed.50 Such a mixture is
consistent with the FMPES results for CBE/BCB below ∼1
nN force, as shown in Figure 4c.
cis-CBE-containing copolymer (P1b) and cis-BCB-contain-
ing copolymer (P2b) were synthesized according to the above
procedure, and the percent incorporation of mechanophore
was determined by 1H NMR to be 18% and 22%, respectively.
Upon application of force, P1B is expected to elongate by
approximately 5% if the E,E-isomer is the sole ring-opened
product and by approximately 4% if the E,Z-isomer is the sole
ring-opened product by CoGEF calculations. Similarly, P2b is
expected to elongate by approximately 5% if the E,E-isomer is
the sole ring-opened product and by approximately 3% in the
E,Z-isomer is the sole ring-opened product. The average
observed elongation by SMFS was 8% and 5% for P1b and
P2b, respectively. On the basis of these observations, it is likely
that these systems are dominated by the disrotatory ring-
opening mechanism; however, we cannot rule out the presence
of some conrotatory ring-opening as well due to the relatively
small changes in contour length of these polymers (see the
Supporting Information for details). Even if the two processes
were equal contributors, the kinetics in this force regime would
only overestimate the rate of the disrotatory reaction by a
factor of 2, and we therefore treat the observed kinetics as a
reliable reflection of the force-coupled energetics of the
forbidden process.
In general, the barriers for conrotatory ring-opening of trans-
cyclobutenes are greater than those of their cis-substituted
analogues, primarily as a result of increased steric hin-
drance.1,51,52 Such is the case here as well; ΔG⧧ for the
force-free conrotatory ring-opening of cis-substituted CBE and
BCB is calculated to be 31.7 and 38.7 kcal/mol, respectively
(Figure 4c), and these barriers are both several kcal/mol higher
than those of their trans analogues. In comparing the
computational results for the two mechanophores, each of
cis- and trans-CBE has a conrotatory ΔG⧧ value lower than
those of its corresponding BCB isomer, as expected due to the
loss of aromaticity in the ring-opening of BCB. Similar to a
recent report by Tian et al.,50 we find that application of
mechanical force across cis-CBE and cis-BCB changes the
potential energy landscape such that two competing ring-
opening processes exist at low forces, a classically allowed
conrotatory path and a classically forbidden disrotatory path.
Computationally, the disrotatory pathways do not exhibit well-
defined transition states until 1.0 nN for cis-CBE and 0.5 nN
for cis-BCB. As external force is increased, the energy barriers
for both conrotatory and disrotatory ring-opening processes
decrease. At forces above 1.0 nN the conrotatory path for cis-
BCB cleanly disappears, leaving only the disrotatory path. In
contrast, the reaction of cis-CBE involves competitive
conrotatory and disrotatory pathways until the conrotatory
barrier disappears at 2.5 nN, at which point the calculated
overall energy barrier is virtually nonexistent.
Both the conrotatory and the disrotatory ring-opening force-
modified potential energy surfaces have similar energetics
around the point expected to correspond with the time scale of
the SMFS experiment (Figure 4c). At this intersection (black
dotted line), the expected activation force of 1.54 nN is
consistent with our SMFS observations (f* ≈ 1.52 nN). The
disappearance of competing saddle points and importance of
reaction dynamics in determining product distribution is an
interesting and increasingly observed phenomenon in force-
coupled reactions.48,50,53 As discussed in the previous para-
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Figure 5. (a) cis-BCB natural orbitals from CASSCF along the B3LYP 2.0 nN FMPES disrotatory reaction coordinate. Here, just the two natural
orbitals with occupation numbers that cross after the transition state are shown. The points indicate structures of reactant, transition state, point of
highest diradical character, and product, respectively. (b and c) Effective number of unpaired electrons along the respective reaction coordinates of
CBE and BCB ring-opening, respectively. For the disrotatory ring-opening reactions of the cis-substituted CBE and BCB, the ENUE maximum is
caused by the crossing of natural orbital occupation numbers.
Figure 6. (a) SMFS of copolymer P1c, which contains both cis- and trans-CBE monomers. (b) SMFS of copolymer P2c, which contains both cis-
and trans-BCB monomers. (c) Activation energy as a function of force for both cis (red)- and trans (blue)-CBE. (d) Activation energy as a function
of force for both cis (red)- and trans (blue)-BCB. The dotted line in both (c) and (d) represents the activation barrier for a generic chemical
reaction that has a rate constant of 10 s−1 at 298 K, which is a reasonable approximation for the rate of ring-opening of the mechanophores during
SMFS experiments. (e,f) Plots showing the dependence of ΔG⧧ on applied force for the allowed (e) and forbidden (f) processes across the force
ranges relevant to the SMFS experiment. Slopes from linear fits (mBCB/CBE) are provided.
graph, a distinct transition state for conrotatory cis-BCB ring-
opening disappears on the FMPES at forces less than those
required to reach the energy barrier where chain extension
competes with tip-stage displacement in the SMFS experiment.
The disrotatory ring-opening pathway, however, remains, and
its expected activation force of 1.04 nN is also consistent with
our experimental observations from SMFS (f* ≈ 1.04 nN).
For the CBE and BCB systems described here, CASSCF
calculations were used to determine the natural orbital
occupancy numbers along the force-free and force-modified
reaction pathways for each cyclobutene isomer pair (Figure
5a). Both trans isomers undergo an allowed conrotatory ring-
opening with a maximum effective number of unpaired
electrons (ENUE) of ∼0.5. Interestingly, the maximum
ENUE along the conrotatory pathway slightly increases as a
function of force, as shown in Figure 5b,c. For the cis isomers,
CASSCF calculations indicate that the forbidden disrotatory
ring-opening processes have peak ENUEs of ∼2, caused by the
crossing of natural orbitals at this point and consistent with a
diradical mechanism. With increasing force, the position of the
transition state shifts toward the reactants (earlier along the
reaction coordinate), and the ENUE maxima along the
disrotatory reaction paths are located after the transition
state structure along the reaction coordinate, which is also in
accordance with the observations of the disrotatory ring-
opening of CBE by Kochar et al.25
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■
▲
Figure 7. (a) Activation barriers as a function of force for both trans-ester BCB (blue ) and trans-alkyl BCB (blue ) mechanophores, calculated
■
▲
as described in the Methods. (b) Activation barriers as a function of force for both cis-ester BCB (red ) and cis-alkyl BCB (red
)
mechanophores. (c) Activation energy as a function of force for both cis (red)- and trans (blue)-alkyl BCB. The dotted line represents the
activation barrier for a generic chemical reaction that has a rate constant of 10 s−1 at 298 K, which is a reasonable approximation for the rate of ring-
opening of the mechanophores during SMFS experiments.
CBE versus BCB and the Allowed/Forbidden Gap.
Figure 6a,b shows representative force versus separation curves
for copolymers P1c and P2c, which contain a mixture of cis-
and trans- isomers of CBE and BCB mechanophores,
respectively. Consistent with what was observed for the
“pristine” copolymers described above, for the mixed
copolymers the trans-CBE mechanophores activate at a lower
f* than do the cis-CBE mechanophores, and conversely the cis-
BCB mechanophores activate at a lower f* than do the trans-
BCB mechanophores. We explain this “flip” in force-modified
reactivity by considering both electronic and mechanical
effects.
We then take the average of the computed (ΔG⧧/df)F and
(ΔG⧧/df)A, along with the experimental plateau forces f*
obtained from Table 1, to obtain a difference in the allowed−
forbidden gap of −10.9 kcal/mol. In other words, ΔGA/F of the
force-coupled BCB ring-opening is about 11 kcal/mol lower
than that of CBE. This difference is in good agreement with
prior work by Sakai, who calculated that ΔGA/F for
unsubstituted BCB (∼8 kcal/mol) is lower than ΔGA/F for
unsubstituted CBE (∼19 kcal/mol) by 11 kcal/mol.17,18 The
difference in the two processes is attributed to the fact that the
symmetry forbidden disrotatory ring-openings of both
unsubstituted CBE17 and unsubstituted BCB18 proceed with
more substantial diradical character than the allowed
analogues, also supported by our calculations.
Without the influence of an external force, the conrotatory
ring-opening of BCB is less favored than the ring-opening of
CBE due to the loss of aromaticity, thus leading to a higher
free energy barrier. For the disrotatory ring-opening of both
CBE and BCB, however, the aromaticity of the benzene ring of
BCB remains intact at the transition state,18 and the loss of
aromaticity lags the formation of diradical character. In fact,
the breaking of aromaticity is accompanied by the recombi-
nation of the two unpaired electrons with the existing π-
system. Thus, dearomatization is not a substantial contributor
to the energy barrier of the disrotatory ring-opening, despite
being responsible for the higher conrotatory ring-opening
energy barrier of BCB than CBE.17,18 Instead, the main
contribution to the potential energy barrier of the disrotatory
processes stems from homolytic scission of the C−C σ bond.
BCB likely has a lower barrier for this C−C bond breaking due
to its greater ring strain relative to CBE.
Ester versus Alkyl Handles. The above contributions of
cis and trans pulling on CBE and BCB mechanophores are
evaluated in the context of ester attachments linking the
mechanophores to the stretched polymer chain, but the nature
of that substituent can have an impact on both the force-free
reactivity and the mechanical coupling. We next consider the
effect of an ester versus an alkyl attachment on BCB ring-
opening, by comparing the results above with previous SMFS
studies of an alkyl-substituted BCB system.32 In that study, the
cis-BCB mechanophore opens at a lower force (f* ≈ 1370 pN)
than the allowed transition of the trans-BCB (f* ≈ 1500 pN),
as was also observed for the ester attachment studied here
(1040 and 1490 pN, respectively).32 Interestingly, the force
gap between the alkyl-substituted cis- and trans-BCB is only
Initially, the calculated force-free activation energy (ΔG⧧) of
the disrotatory mechanism for both cis mechanophores is
higher than the ΔG⧧ of the conrotatory mechanism for both of
the corresponding trans mechanophores. As the applied force
is increased, the energy barriers for cis mechanophores
decrease more quickly than do the energy barriers for trans
mechanophores, and each mechanophore pair exhibits a
crossover force, above which the energy barrier for the
disrotatory ring-opening of the cis mechanophore is lower than
that of the conrotatory ring-opening of trans mechanophores
(Figure 6c,d). The calculated crossover force for CBE is ∼2.36
nN, well above the force necessary to reach the ∼16.6 kcal/
mol barrier probed in the SMFS experiment (black line). In
contrast, the calculated crossover force for BCB is ∼0.74 nN,
which is less than the force relevant to SMFS.
The combined computational and experimental data can be
used to assess how the structural change on going from CBE to
BCB influences the allowed-forbidden gap ΔGA/F. Because
their structures and reaction paths are quite similar, the cis-
CBE and cis-BCB mechanophore reaction paths are expected
to be coupled in nearly identical ways to the applied force. This
expectation is borne out by the computations, which show that
the force-coupled change in the activation energy of the
forbidden process, (ΔG⧧/df)F, is −20.0 and −16.5 kcal mol−1
nN−1 for BCB and CBE, respectively, across the force ranges
relevant to SMFS (Figure 6f). The corresponding values
(ΔG⧧/df)A for the allowed processes are −9.4 and −9.6 kcal
mol−1 nN−1 (Figure 6e). The difference in the allowed−
forbidden gap can then be estimated as follows:
⧧
⧧
*
*
*
*
− fA
(BCB)
ΔGA/F = (fF
− fF )·(ΔG /df )F − (f
)
A(CBE)
(CBE)
(BCB)
·(ΔG⧧/df )
A
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∼130 pN, in comparison to the ∼450 pN force gap observed
here in the corresponding ester-substituted BCBs (Table 1).
The greater reactivity of cis- relative to trans-BCB in the
force-coupled reactions of ester versus alkyl-substituted BCB is
due to mechanical, rather than (or despite) intrinsic electronic
effects. Figure 7 shows plots of the calculated ΔG⧧ versus
applied force for cis/trans alkyl-substituted BCB mechano-
phores, analogous to the calculations for ester-substituted CBE
and BCB reported above. The force-free activation energy
(ΔG⧧) of trans-alkyl BCB is ∼6 kcal mol−1 higher in energy
(36.1 kcal mol−1) than that of trans-ester BCB (29.9 kcal
mol−1). Such stabilization is consistent with the findings of
Niwayama et al., who found that electron-donating sub-
stituents lower the activation barrier of the conrotatory ring-
opening of cyclobutenes.9 As more force is applied across the
trans attachments, however, the difference in activation
energies shrinks until it is virtually identical at the transition
force required for activation on the time scale probed in the
SMFS experiment, which is in line with our experimental
results (f* = 1500 vs 1490 pN for alkyl and ester attachments).
The enhanced mechanical leverage of dialkyl relative to diester
attachments is consistent with calculations reported previously
by Tian et al. on trans-cyclobutene derivatives.54
of force than are their allowed counterparts, but (as observed
here for the BCB mechanophore) they can outpace the
competing allowed reactions at forces relevant to mechano-
chemical response. For example, replacing alkyl handles with
ester handles, as shown here, both slows the force-free reaction
and accelerates the force-coupled reaction. Additional studies
of substituent effects on competing force-coupled reaction
pathways are therefore likely to be quite productive.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12088.
■
sı
Experimental procedures, spectroscopic data, SMFS, and
computational details (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Stephen L. Craig − Department of Chemistry, Duke
University, Durham, North Carolina 27708, United States;
orcid.org/0000-0002-8810-0369; Email: stephen.craig@
duke.edu
As with the cis-ester BCB, the cis-alkyl BCB does not have a
computational first-order saddle point for disrotatory ring-
opening at 0 nN, but the trends in reactivity as a function of
force provide some insight. In particular, we note that in
contrast to the trans-BCBs, the cis-ester BCB is accelerated
more with increasing force than is the cis-alkyl BCB. The two
derivatives are similar in reactivity at low force, but the ester is
more reactive at high force. In other words, at low force the
preference for the allowed pathway is greatest for the diester
BCBs, but the preference diminishes with increasing force
more rapidly for the ester substituents and ultimately reverses
at lower force than in the dialkyl analogues.
Todd J. Martinez − Department of Chemistry, Duke
University, Durham, North Carolina 27708, United States;
SLAC National Accelerator Laboratory, Menlo Park,
California 94025, United States; orcid.org/0000-0002-
4798-8947; Email: todd.martinez@stanford.edu
Authors
Cameron L. Brown − Department of Chemistry, Duke
University, Durham, North Carolina 27708, United States;
orcid.org/0000-0002-9616-2084
Brandon H. Bowser − Department of Chemistry, Duke
University, Durham, North Carolina 27708, United States;
orcid.org/0000-0002-8313-9301
Jan Meisner − Department of Chemistry and The PULSE
Institute, Stanford University, Stanford, California 94305,
United States; SLAC National Accelerator Laboratory,
Menlo Park, California 94025, United States; orcid.org/
0000-0002-1301-2612
Tatiana B. Kouznetsova − Department of Chemistry, Duke
University, Durham, North Carolina 27708, United States
Stefan Seritan − Department of Chemistry and The PULSE
Institute, Stanford University, Stanford, California 94305,
United States; SLAC National Accelerator Laboratory,
Menlo Park, California 94025, United States; orcid.org/
0000-0002-8808-6886
CONCLUSION
■
In summary, we have quantified force-coupled reactivity of
CBE and BCB along conrotatory and disrotatory pathways via
single-molecule force spectroscopy. These experimental results
provide an important benchmark for calculations, and the
agreement supports the validity of the computational method-
ology for these and similar reactions going forward. The results
provide insights into the energetics of allowed and forbidden
reactivity, and the difference in the so-called allowed/
forbidden gap for BCB is lower than that for CBE, as inferred
from force-coupled reactions. Similar methodology could be
used for other structure−reactivity relationships in CBEs or
related reaction classes.
In addition to the electronics of the conjugated π system,
substituent effects at the pulling attachment are shown to be
important, with trans-alkyl handles providing more mechanical
leverage than do trans-ester handles in conrotatory reactions,
while cis-ester handles provide more mechanical leverage than
do cis-alkyl handles in disrotatory reactions. Understanding
these various influences is important beyond just under-
standing fundamental questions of reactivity, because mecha-
nophores that react through electrocyclic reactions are of
increasing interest for applications such as self-healing/
strengthening,55−57 stress-reporting,58−62 and mechanoacid
generation.34,63,64 We speculate that mechanophores that
react via forbidden pathways are especially intriguing, because
forbidden reactions are intrinsically more inert in the absence
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12088
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This material is based on work supported by the National
Science Foundation under grant CHE-1808518 (S.L.C.) and
by the U.S. Army Research Office under grant no. W911NF-
15-1-0525 (T.J.M.). C.L.B. acknowledges support from the
National Science Foundation Graduate Research Fellowship
Program under grant no. DGE-1106401 and the Dean’s
Graduate Fellowship from Duke University. J.M. thanks the
Dr.-Leni-Schöninger foundation and the Deutsche Forschungs-
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