Tilting a ground-state reactivity landscape by vibrational strong coupling

Article abstract of DOI:10.1126/science.aau7742

Many chemical methods have been developed to favor a particular product in transformations of compounds that have two or more reactive sites. We explored a different approach to site selectivity using vibrational strong coupling (VSC) between a reactant and the vacuum field of a microfluidic optical cavity. Specifically, we studied the reactivity of a compound bearing two possible silyl bond cleavage sites—Si–C and Si–O, respectively—as a function of VSC of three distinct vibrational modes in the dark. The results show that VSC can indeed tilt the reactivity landscape to favor one product over the other. Thermodynamic parameters reveal the presence of a large activation barrier and substantial changes to the activation entropy, confirming the modified chemical landscape under strong coupling.

Full text of DOI:10.1126/science.aau7742

RESEARCH
tuned in resonance with the chosen molecular
transition (21). When the exchange of energy
between the molecular transition and cavity
mode is faster than any decay process, the system
is said to be in a strong coupling regime man-
ifested by the splitting of the molecular transi-
tion into two new states separated by a Rabi
CHEMISTRY
Tilting a ground-state reactivity
landscape by vibrational
strong coupling
splitting energy, ħW
stant h divided by 2p and W
R
(where ħ is Planck’s con-
is the Rabi fre-
R
quency), as shown schematically in Fig. 1A with
VSC as a specific example. Strong coupling
strength and therefore the Rabi splitting in-
creases as the square root of the concentration
of coupled molecules (21). Under such collective
strong coupling conditions, the Rabi splitting
can be so large that it results in substantial
modification of characteristic properties beyond
chemical reactivity, such as electrical conduc-
tivity (22), rates of energy transfer (23, 24), and
reverse intersystem crossing (25). This has led
to many experimental and theoretical studies of
strongly coupled molecular systems [for example,
1
1
1
1
1
A. Thomas *, L. Lethuillier-Karl *, K. Nagarajan , R. M. A. Vergauwe , J. George †,
1
2
1
1
1
1
T. Chervy ‡, A. Shalabney , E. Devaux , C. Genet , J. Moran §, T. W. Ebbesen §
Many chemical methods have been developed to favor a particular product in transformations
of compounds that have two or more reactive sites. We explored a different approach to
site selectivity using vibrational strong coupling (VSC) between a reactant and the vacuum field
of a microfluidic optical cavity. Specifically, we studied the reactivity of a compound bearing
two possible silyl bond cleavage sites—Si–C and Si–O, respectively—as a function of VSC
of three distinct vibrational modes in the dark. The results show that VSC can indeed tilt the
reactivity landscape to favor one product over the other.Thermodynamic parameters reveal the
presence of a large activation barrier and substantial changes to the activation entropy,
confirming the modified chemical landscape under strong coupling.
(26–38)]. For those not familiar with light-matter
strong coupling, it might be understood through
analogy with the concept of a charge transfer com-
plex. Whereas electrons are shared between two
moieties in a charge transfer complex, in light-
matter strong coupling, photons are shared be-
tween the cavity and the molecules. Although it
is well established that in the first case, chemical
properties change, we demonstrate again that
this is also the case for strong coupling. A de-
tailed introductory explanation of strong cou-
pling of molecules is available in (21).
The Fabry-Pérot cavity used in the present ex-
periments comprised two parallel metal mirrors
(Au-coated ZnSe) separated by Mylar spacers of
different thicknesses (6 to 8 mm), with a hollow
central channel designed to inject liquid samples
(15). To ensure that the reaction dynamics were
not affected by the presence of Au or ZnSe, an
ver the years, synthetic chemists have re-
fined the art of designing and developing
bond-, site-, and stereoselective chemical
reactions using various functional moieties
and catalysts. In light of the decisive nature
tromagnetic field of a cavity by means of vi-
brational strong coupling (VSC) (13–16). In other
words, even in the dark, the zero-point energy
fluctuations of the cavity mode can interact
with the vibrational transition and lead to the
formation of two new vibropolaritonic states
(Fig. 1A, P+ and P–) that should affect the Morse
potential. We predicted that this splitting could
lead to changes in chemical reactivity (17) and
demonstrated that the rate of silyl cleavage in
1-phenyl-2-trime-thylsilylacetylene is reduced
through VSC of the Si–C stretching vibration
(18). The reaction mechanism was also modified.
Changing the ground-state reactivity land-
scape under such a weak-field perturbation
suggests that VSC could also be used to modify
site selectivity. In a proof-of-principle study, we
demonstrate that it is indeed possible to tilt the
chemical landscape of a reactant to favor one
product over another.
To explore the above possibilities, we synthe-
sized the silane derivative, tert-butyldimethyl{[4-
(trimethylsilyl)but-3-yn-1-yl]oxy}silane (called R
hereafter) (Fig. 1B), which incorporates two dis-
tinct sites for prospective silyl bond cleavage
(supplementary materials) (19, 20). Nucleophilic
attack by a fluoride ion on either Si atom can
result in the respective cleavage of the Si–C bond,
yielding product 1, or the Si–O bond, yielding
product 2 (Fig. 1B). Because both products form
through similar mechanistic pathways, we ex-
plored first whether the selective strong coupling
of vibrational modes respectively associated with
Si–C and Si–O has similar or different influences
on the reactivity. The second and most important
point of the present study was to ascertain
whether changes in the reactivity landscape
under VSC lead to site selectivity and thereby
changes to the branching ratio of the products as
schematically presented in Fig. 1, B and C.
O
of molecular vibrations in dictating the outcome
of isomerization and other chemical processes
1–3), a physical approach based on the selective
(
excitation of vibrational modes by using strong
laser fields has also been explored to impart con-
trol on chemical reactivity (4–7). This laser-
induced mode-selective chemistry aimed to steer
the system along the reaction coordinate and
appeared most straightforward for late barrier
reactions (8, 9). The vibrational excitation of the
C–H bond of an early barrier reaction inhibited
formation of the typical product and modified
the branching ratio (10), even though such an
excitation was predicted to have little influence
on the outcome (11). An adiabatic transfer of
excitation to the product stretching mode was
also observed when the localized spectator mode
of the reactant was pumped in the former ex-
periments, further indicating the complexities
of the reactive landscape (10, 12). Although such
mode-selective chemistry works well in the gas
phase at cryogenic temperatures, intramolecular
vibrational energy redistribution (IVR) limits
its use for reactions in solution involving large
molecules. To overcome such challenges, we
started exploring an alternative approach in
which the vibrational transition of a molecule
is selectively hybridized with the vacuum elec-
2
additional 200-nm-thick layer of glass (SiO ) was
deposited on the inner surface of each window.
A homogeneous solution of the starting material
R (0.90 M) and tetrabutylammonium fluoride
(TBAF; 0.86 M) in a 1:1 (v/v) mixture of methanol
and tetrahydrofuran (THF), optimized for strong
coupling conditions by using a high concentra-
tion of R to achieve the highest Rabi splittings,
was used as the reaction medium throughout the
experiments presented here. The infrared (IR)
spectrum of R (Fig. 2A) in this mixture recorded
outside the cavity shows the characteristic strong
−1
bands corresponding to the Si–C (842 cm ) and
−1
Si–O (1110 cm ) stretching modes and the bending
−1
3
mode of the CH groups bonded to Si (1250 cm ).
VSC requires the cavity mode to be in reso-
nance with a specific IR transition of R. This
was achieved through careful adjustment of
the spacer thickness by tightening or loosening the
screws holding the assembly together to vary
the applied pressure (supplementary materials).
Injection of the homogeneous reaction mixture
into the flow cell Fabry-Pérot cavity, whose sec-
1
University of Strasbourg, CNRS, ISIS and icFRC, 8 allée G.
2
Monge, 67000 Strasbourg, France. Braude College, Snunit
Street 51, Karmiel 2161002, Israel.
These authors contributed equally to this work. †Present address:
Department of Chemical Sciences, Indian Institute of Science
Education and Research Mohali, Mohali, India. ‡Present address:
Institute for Quantum Electronics, ETH Zürich, CH-8093 Zürich,
Switzerland.
*
−1
Light-matter hybridization is generally achieved
by placing molecules in the liquid or solid phase
into a Fabry-Perot optical cavity with a mode
ond mode (l) was precisely tuned to 842 cm ,
resulted in the strong coupling of the Si–C stretch-
ing transition (Fig. 2B). The appearance of P+
§
Corresponding author. Email: ebbesen@unistra.fr (T.W.E.);
moran@unistra.fr (J.M.)
Thomas et al., Science 363, 615–619 (2019)
8 February 2019
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RESEARCH
| REPORT
through a small aperture in the central tuned
area. A higher product ratio (0.4 ± 0.1) was ob-
served when the Si–O stretching vibration was
strongly coupled. Thus, VSC of the stretch vi-
bration at either site modifies the reactive land-
scape in favor of Si–O cleavage over the otherwise
kinetically favored Si–C cleavage.
As discussed earlier, previous mode-selective
chemistry experiments have shown that spec-
tator modes—vibrations that are not directly
linked to the reaction coordinate—also play a
critical role in determining reaction outcomes
(
10, 41). In the present case, the strong IR band
−1
at 1250 cm , arising from the bending mode of
the CH
–
3
groups bonded to Si (42), can be con-
sidered a spectator vibration. However, the
−
1
appearance of this IR transition at 1250 cm
,
−
1
which one would normally expect at ~1460 cm
–
if it is an isolated CH
3
group, already indicates
Fig. 1. Test reaction to probe the influence of VSC on site selectivity. (A) Schematic illustration
of the light-matter strong coupling of a vibrational transition in resonance with Fabry-Pérot cavity
mode and the subsequent formation of hybrid polaritonic states P+ and P– separated by Rabi
splitting energy, ħWR. (B) The two major silyl cleavage pathways (Si–C scission to form 1, Si–O
scission to form 2) for the reaction of R with TBAF in a room-temperature mixture of methanol and
THF. (C) Schematic representation of competing site-selective pathways upon VSC of the reactant.
that it is interacting with other vibrations as-
sociated with the Si center. By varying the spacer
thickness, we achieved VSC of this bending mode
−1
R
alone (Fig. 2D) with a ħW of 43 cm , without
simultaneously coupling either the Si–C or Si–O
−1
stretching vibrations. VSC of the 1250 cm vi-
bration reduced the overall reaction rate by a fac-
tor of 3.5 ±0.1 (Fig. 2E, magenta triangle), which
is in close similarity to the results obtained under
VSC of the Si–C stretching transition and gave
rise to a product ratio [1]/[2] of 0.3 ± 0.1 (Fig. 2F,
magenta chromatogram). The question then
arises whether the VSC of any vibrational mode
of R would lead to similar results or whether the
effects are restricted to those vibrations that are
associated with the reactive Si centers. To explore
this question, we coupled the cavity to the C–O
and P– peaks in the IR spectrum with a ħW
R
diamond) by a factor of 3.5 ± 0.2 compared
with the control measurements done outside
the cavity (Fig. 2E, blue triangle) or inside the
cavity under off-resonance conditions (Fig. 2E,
green square), when the cavity was not tuned to
any of the selected vibrational transitions of R.
Similarly, strong coupling to the Si–O stretch
to the cavity slowed the overall rate by a factor
of 2.5 ± 0.1 relative to the outside cavity/off
resonant conditions (Fig. 2E, orange circle). The
error margin was determined from the standard
deviation of a minimum of five experiments.
The reaction mixtures were quantitatively
analyzed by means of gas chromatography–mass
spectrometry (GC-MS) after each experiment
(supplementary materials). The presence of un-
reacted starting material (labeled R in fig. S9) in
all the chromatograms showed that the reaction
was far from completion in the 3-hour time
period and that the ratio did not change over
time within the limits of the experiments. The
ratios ([1]/[2]) of the Si–C cleavage to Si–O
cleavage product concentrations were further
quantified from the GC-MS. For outside cavity
and off-resonance reactions, the ratios favored
Si–C cleavage and were equivalent within exper-
imental error (1.5 ± 0.2 and 1.4 ± 0.1, respec-
tively). A remarkable increase in the peak area
of product 2 was seen when the Si–C stretching
vibration was strongly coupled (Fig. 2F, red
chromatogram), with a modified branching ratio
[1]:[2] of 0.3 ± 0.1. This value takes into account
the fraction of the Fabry-Perot microfluidic cavity
under strong coupling. As explained in the sup-
plementary materials, ~60% of the cavity is under
VSC because of the deformation of the mirrors
when the cavity is tuned by applying pressure
with screws. The remaining 40% is detuned be-
yond the width of the vibrational mode and, as a
consequence, is in the off-resonance condition.
At the same time, the reaction rate is monitored
−
1
of 70 cm , larger than the width of the cavity
−
1
mode (30 cm ) and the Si–C vibrational band
−
1
(
30 cm ), showed that the system meets the
strong coupling criteria (21). Under these con-
ditions, we also observed a largely detuned
coupling between the bending mode of the
; 1250 cm−
1
)
CH
3
groups bonded to Si (Si–CH
3
and the third mode of the cavity. The influence of
the strongly coupled Si–CH bending vibration
3
−1
on the reactivity was analyzed separately and is
described later. In a different experiment, VSC
of the Si–O stretching band was achieved by
tuning the third mode of the cavity to 1110 cm−
stretching transition (at 1045 cm ) of R, a vi-
bration that should have little influence on the
reaction from a mechanistic point of view. This
mode is also embedded in the broad region (1040
1
−1
(
Fig. 2C, solid line). The presence of the intense
to 1060 cm ) (Fig. 2A) corresponding to the C–O
vibrations of the solvents used (methanol and
THF) and so should also serve as a probe of
whether coupling to a solvent vibration in-
fluences the outcome of the reaction. We ob-
served that neither the rate nor the product
ratio was affected by VSC of this C–O transition
(fig. S10).
and broad vibrational modes of the solvents (1040
−1
to 1060 cm ) splits and reduces the P– band in-
tensity (Fig. 2C) and complicates the spectrum
analysis. Therefore, we calculated the ħW in this
R
case using the standard optics technique (transfer
matrix simulation, as explained in the supple-
mentary materials) (Fig. 2C, dotted line). The
−1
extracted value of 85 cm is well above the cavity
and IR mode widths.
We completed these experiments by measur-
ing the overall observed reaction rate (kobs) as a
function of cavity tuning across the IR spectrum
of R to obtain an action spectrum (Fig. 3A) that
clearly confirms which vibrational modes in-
fluence the reaction under VSC. This plot reflects
the precise selectivity that can be achieved by this
weak-field physical perturbation tool at room
temperature. Tuning the cavity so that VSC oc-
curs at normal incidence is essential to observe
the modification of chemical properties. In this
condition, the system is at the minimum energy
in the polaritonic state.
By combining the observed overall rate con-
stant (kobs) of the parallel reaction and the prod-
uct ratios ([1]/[2]) from GC-MS measurements,
we estimated the individual rate constants cor-
1 2
responding to the Si–C (k ) and Si–O (k ) bond
scissions. From the data, the respective product
The sum rates of the two parallel silyl cleavage
reactions under the influence of VSC were
quantitatively determined from the ln plot of
the temporal shift of a higher-order cavity mode
(
from ꢀn 0 to ꢀn t) (supplementary materials). Similar
to the earlier experiment (18), this analysis was
aided by the slight change in the refractive in-
dices of the reactant and products. The linearity
of the ln plot (Fig. 2E) supported first-order
kinetics, and from the slope, the rate constant
corresponding to the disappearance of starting
material was determined. The observed first-
order kinetics for this bimolecular reaction is
an indication of a complex reaction mechanism,
as documented in the literature (39, 40). When
the Si–C stretching bond vibration was strongly
coupled, the rate was retarded (Fig. 2E, red
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Fig. 2. VSC spectra and relative bond scission
kinetics. (A) Fourier transform IR (FTIR) trans-
mission spectrum of the starting material
R in the reaction mixture recorded in a sample
cell, with glass-coated ZnSe windows separated
by the same spacer thickness as of the Fabry-
Pérot cavity. (B to D) FTIR transmission spectra
showing P+ and P– splitting when the three
different modes are strongly coupled to the
cavity. (B) The Si–C stretching mode. (C) The
Si–O stretching mode together with a transfer
matrix simulated transmission spectrum
(
black dotted line). (D) Si–CH
3
bending vibration.
(
E) Kinetics of the reactions in cavities tuned
to be on-resonance with the Si–C stretching
red diamonds), the Si–O stretching (orange
circles), and the Si–CH bending modes
magenta triangles), together with the data for
(
3
(
an off-resonance cavity (green squares) and
outside the cavity (blue triangles), as extracted
from the temporal shifts in the higher-order
cavity modes. The error bars show the standard
deviations for a minimum of five independent
experiments for each case. (F) The GC-MS
chromatograms of the reactions carried out in
cavities tuned to be on-resonance with Si–C
stretching (red), Si–O stretching (orange), and
Si–CH bending modes (magenta), together
3
with the data for an off-resonance cavity (green)
and outside the cavity (blue). The peaks
corresponding to C- and O-deprotected products
are marked as 1 and 2, respectively. The peak
indicated by the arrow is an impurity that comes from the slow degradation of the GC-MS column and is present in all the chromatograms that we
measured. These chromatograms are zoomed in on the products for clarity; the complete ones can be found in fig. S9.
yields were calculated. The yields (f) of products
1
and 2 in and out of strong coupling for various
coupling conditions are shown in Fig. 3B. Out-
side the cavity and in off-resonance conditions,
the k dominates over k , resulting in preferential
1 2
formation of product 1 (Fig. 3B, purple diamond).
VSC reverses the selectivity, leading to an excess
formation of product 2 (Fig. 3B, pink squares).
This is again a direct proof of principle that the
chemical landscape can be tilted by targeting
the three vibrational modes associated with the
1 2
reaction centers. The values of both k and k
under strong coupling conditions are lower than
those observed outside the cavity, indicating that
a higher activation energy is required for the re-
action under VSC. Products 1 and 2 undergo fur-
ther silyl bond cleavage, although the subsequent
reactions appear to be much slower, resulting
in the accumulation of 1 and 2 in the GC-MS
analysis. These downstream reactions impart a
small error in the yields but have no consequence
on the overall results.
Fig. 3. Relative VSC influence across the vibrational spectrum. (A) The overall reaction rate
as a function of cavity tuning for reactions inside the cavity (red spheres). The blue solid line
shows the IR absorption spectrum of R in the reaction medium. The red dotted line connecting the
spheres is a guide for the eye. The blue dashed line represents the average rate of the reaction
1 2
outside the cavity. (B) Plot showing the yields of product 1 (f ; violet diamonds) and 2 (f ; pink
squares) under VSC of various vibrational modes of R, together with the off-resonance and outside
cavity conditions. The error margin was determined from the standard deviation of a minimum
of five experiments in each case.
The thermodynamics of the two bond-breaking
reactions that lead to products 1 and 2 were
determined by measuring the rates as a function
of temperature under VSC of the Si–C and Si–O
stretching vibrations as well as outside the cavity.
Using transition state theory, the free energy of
temperature (Fig. 4). The results extracted from
the plots of Fig. 4 are summarized in Table 1. It
shows that the thermodynamic parameters are
substantially changed under VSC for both products
but lead to different values for products 1 and 2.
the Si–C or the Si–O stretching vibrations. This
might be fortuitous for the specific molecule
under study. It has been shown that the presence
of leaving groups far away can change desilyla-
tion rates (43).
‡
activation (DH ) and the entropy of activation
‡
‡
(
DS ) were determined from the slope and inter-
What is surprising is that the new values of DH
The above results show that VSC can modify
‡
‡
cept of the plot of ln(k) against the inverse of
and DS appear to be similar whether one couples
the chemical landscape, and the associated DH
Thomas et al., Science 363, 615–619 (2019)
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RESEARCH
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coupling for enhancing site selectivity of organic
and inorganic chemical reactions. More reactions
must be studied to evaluate the generality of this
phenomenon and to see to what extent the se-
lectivity can be enhanced at a given site. As more
and more studies show, this weak-field room-
temperature method has the potential to become
an everyday tool for chemists to physically con-
trol chemical reactivity without catalysts, pre-
functionalization, or chemical changes to the
reaction conditions.
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and DS , in such a way that it tilts the landscape
from one product to another. An interesting
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has been the high activation barrier seen toward
the breaking of Si–C and Si–O bonds. Because a
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to proceed through an associative mechanism
involving a pentacoordinate intermediate (39), a
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electronic strong coupling, such as in the photo-
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strained transition state with large negative DS
is expected as observed outside the cavity. The
observed sharp decrease of DS to a lower value
under VSC implies that the transition state is
strongly modified, particularly the one leading to
product 2. The high activation energy and the
4
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3
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1
3
3
3
2
‡
less negative DS clearly indicate that the reac-
This proof-of-principle study shows that it is
possible to control reaction selectivity through
VSC. Strong coupling is dependent on the orienta-
tion of the transition dipole moment relative to
the electric field of the cavity mode. The molecules
were randomly oriented, and the electric field was
not uniform in the cavity; there were nodes where
the field was essentially null. Hence, the fivefold
increase in selectivity under VSC reported here
is probably much larger if corrected for such fea-
tures. For instance, experiments could be done
in a tubular cavity to ensure a larger fraction of
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bond cleavage, allowing otherwise slower dis-
sociative pathways to dominate. The stronger
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earlier experiments, whether occurring in the
Thomas et al., Science 363, 615–619 (2019)
8 February 2019
4 of 5

RESEARCH
| REPORT
4
4. H. Hiura, A. Shalabney, J. George, ChemRxiv 10.26434/
chemrxiv.7234721.v2 (2018).
T.W.E. and J.M. both acknowledge the support of the ERC
(project 788482 MOLUSC and 639170 CarbonFix, respectively).
Author contributions: A.T. and L.L.-K. took the lead in
all the experiments, assisted by K.N., R.M.A.V., J.G.,
T.C., A.S., and E.D.; C.G. provided theoretical insight, and
J.M. and T.W.E. conceived and oversaw the experiments.
Competing interests: The authors declare no competing interests.
Data and materials availability: All data are available in the
main text or the supplementary materials.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/363/6427/615/suppl/DC1
Materials and Methods
Figs. S1 to S10
Table S1
ACKNOWLEDGMENTS
Funding: We acknowledge support of the International Center for
Frontier Research in Chemistry (icFRC, Strasbourg), the ANR
Equipex Union (ANR-10-EQPX-52-01), the Labex NIE projects
Reference (45)
(ANR-11-LABX-0058 NIE), and CSC (ANR-10-LABX- 0026 CSC)
13 July 2018; accepted 8 January 2019
10.1126/science.aau7742
within the Investissement d’Avenir program ANR-10-IDEX-0002-02.
Thomas et al., Science 363, 615–619 (2019)
8 February 2019
5 of 5

Tilting a ground-state reactivity landscape by vibrational strong coupling
A. Thomas, L. Lethuillier-Karl, K. Nagarajan, R. M. A. Vergauwe, J. George, T. Chervy, A. Shalabney, E. Devaux, C. Genet, J.
Moran and T. W. Ebbesen
Science 363 (6427), 615-619.
DOI: 10.1126/science.aau7742
Shaking up reaction-site selectivity
It seems intuitive that putting vibrational energy into a chemical bond ought to promote selective cleavage of that
bond. In fact, the relation of vibrational excitation to reactivity has generally proven subtler and more complex. Thomas
et al. studied how strong coupling of specific vibrational modes to an optical cavity might influence a molecule with two
competing reactive sites. The molecule had two silicon centers that could react with fluoride by respective cleavage of a
Si−C or Si−O bond. Exciting the vibrations at either center slowed down the overall reaction while favoring otherwise
disfavored Si−O cleavage.
Science, this issue p. 615
ARTICLE TOOLS
http://science.sciencemag.org/content/363/6427/615
SUPPLEMENTARY
MATERIALS
http://science.sciencemag.org/content/suppl/2019/02/06/363.6427.615.DC1
REFERENCES
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