Modulation of Prins Cyclization by Vibrational Strong Coupling

Article abstract of DOI:10.1002/anie.201915632

Light-molecule strong coupling has emerged within the last decade as a new method to control chemical reactions. A few years ago it was discovered that chemical reactivity could be altered by vibrational strong coupling (VSC). Only a limited number of reactions have been investigated under VSC to date, including solvolysis and deprotection reactions. Here the effect of VSC on a series of aldehydes and ketones undergoing Prins cyclization, an important synthetic step in pharmaceutical chemistry, is investigated. A decrease of the second-order rate constant with VSC of the reactant carbonyl stretching groups is observed. We also observe an increased activation energy due to VSC, but proportional changes in activation enthalpy and entropy, suggesting no substantive change in reaction pathway. The addition of common cycloaddition reactions to the stable of VSC-modified chemical reactions is another step towards establishing VSC as a genuine tool for synthetic chemistry.

Full text of DOI:10.1002/anie.201915632

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Modulation of Prins Cyclization by Vibrational Strong Coupling
Authors: Kenji Hirai, Rie Takeda, James A. Hutchison, and Hiroshi Uji-i
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915632
Angew. Chem. 10.1002/ange.201915632
Link to VoR: http://dx.doi.org/10.1002/anie.201915632
http://dx.doi.org/10.1002/ange.201915632

10.1002/anie.201915632
Angewandte Chemie International Edition
COMMUNICATION
Modulation of Prins Cyclization by Vibrational Strong Coupling
Kenji Hirai,*[a,b,c] Rie Takeda,[a, b] James A. Hutchison,[d] and Hiroshi Uji-i*[a,c,e]
Abstract: Light-molecule strong coupling has emerged within the
last decade as an entirely new method to control chemical reactions.
A few years ago it was discovered that the chemical reactivity could
be altered by vibrational strong coupling (VSC). While the potential
of VSC in organic chemistry appears enormous, only a limited
number of reactions have been investigated under VSC to date,
including solvolysis and deprotection reactions. Here we investigate
the effect of VSC on a series of aldehydes and ketones undergoing
Prins cyclization, an important synthetic step in pharmaceutical
chemistry. We observe a decrease of the second-order rate constant
with VSC of the reactant carbonyl stretching groups. We measure an
increased activation energy due to VSC, but proportional changes in
activation enthalpy and entropy suggest no substantive change in
reaction pathway. The addition of common cycloaddition reactions to
the stable of VSC-modified chemical reactions is another step
towards establishing VSC as a genuine tool for synthetic chemistry.
N is the number of material oscillators present (Fig.1).[6–8] A few
years ago it was discovered that, even in the absence of laser
pumping of the optical cavity (the vacuum field regime), VSC
influences the kinetics of organic reactions.[10–14] The kinetic
changes are attributed to the vibro-polariton states, potentially
reshaping the Morse potential of molecules and leading to the
altered chemical reactivity.[9] To date, studies on VSC chemistry
have been reported in deprotection[10,11], solvolysis,[12–14] and
addition reactions.[12] Although recent work showed the utility of
VSC in organic reactions, the field awaits comprehensive
expansion to demonstrate its application for versatile reactions
commonly used in organic chemistry.
Much of organic chemistry is focused on reactions that
form carbon-carbon bonds to yield target products. For example,
the Prins cyclization[15–17] is a common cycloaddition reaction
that enables the synthesis of cyclic carbon compounds from two
or more reactants. The reaction rate of the Prins cyclization is
mainly determined by the ease of nucleophilic (e.g., carbon-
carbon double bond) attack on the protonated carbonyl of an
aldehyde or ketone.[18,19] This rate-limiting step is strongly
dependent on the reactivity of the carbonyl group.
Herein we demonstrate that VSC of the aldehyde/ketone
carbonyl stretching band can be used to control (slow) the rate
of Prins cyclization. Temperature dependent studies point to an
increased activation energy due to VSC, but no substantive
change in mechanistic pathway, with relative changes in
activation entropy and enthalpy being similar. This work further
demonstrates the versatility of VSC as a tool to modulate
organic reactions since the key mechanism, nucleophilic attack,
is one of the most common in organic synthesis. This work may
thus inspire the application of VSC to a much larger range of
organic synthetic reactions.
In the last several decades, strong coupling between light
and matter has been explored in a wide range of materials, from
single atoms to proteins,[1–3] and over broad frequency ranges,
from UV to terahertz. [4,5] In all these contexts, the criterion for
strong coupling is the reversible exchange of energy between
the material absorption and an optical resonance that is faster
than any loss mechanisms. Vibrational strong coupling (VSC) of
organic molecules is typically achieved using a Fabry-Pérot (FP)
cavity with mirrors tuned with ~micron separation to be resonant
with the molecular vibrational absorption bands. The resulting
hybrid ‘vibro-polariton’ states exhibit a splitting of the normal
mode vibration (the Rabi splitting, ħΩ) proportional to √N, where
[a]
Prof. Dr. K. Hirai, R. Takeda, Prof. Dr. H. Uji-i
Division of Photonics and Optical Science, Research Institute for
Electronic Science (RIES)
Hokkaido University
North 20 West 10, Kita ward, Sapporo, Hokkaido, Japan
E-mail: hirai@es.hokudai.ac.jp
[b]
[c]
Prof. K. Hirai, R. Takeda
Precursory Research for Embryonic Science and Technology
(PRESTO)
Japan Science and Technology Agency (JST)
4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Prof. Dr. K. Hirai, Prof. Dr. H. Uji-i
Division of Information Science and Technology, Graduate School of
Information Science and Technology
Hokkaido University
North 14 West 9, Kita ward, Sapporo, Hokkaido, Japan
Dr. James A. Hutchison
School of Chemistry
The University of Melbourne
Masson Rd, Parkville VIC 3052, Australia.
Prof. Dr. H. Uji-i
[d]
[e]
Department of Chemistry
Katholieke Universiteit Leuven
200F, 3001 Heverlee, Leuven, Belgium.
E-mail: hiroshi.ujii@kuleuven.be
Figure 1. (a) Schematic energy levels of vibro-polaritonic states formed from
the coupling of a molecular vibrational transition and a FP cavity mode, (the
Rabi splitting, ħΩ indicated). (b) Prins cyclization in the presence of I2.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201915632
Angewandte Chemie International Edition
COMMUNICATION
We prepared a FP cavity consisting of two parallel mirrors
separated by Kapton film. The mirrors were fabricated by
sputtering Au onto ZnSe windows. The Au-sputtered mirrors
were further protected by applying a spin-coated film of silicon
resin (Fig. S1). Acetaldehyde mixed in dichloromethane was
placed in the prepared FP cavity. The spacing between the
mirrors was precisely tuned by fine-pitched microscrews to
couple an optical cavity mode with the carbonyl stretching
vibration of acetaldehyde. The 6th order cavity mode was
coupled to the carbonyl stretching vibration of acetaldehyde to
form two new vibro-polaritonic states, denoted as P+ and P- (Fig.
2a). The Rabi splitting energy between P+ and P- (105 cm-1)
was larger than both the carbonyl stretching vibration (FWHM =
27 cm-1) and the optical cavity mode (FWHM = 54 cm-1). This
result suggests that VSC of the carbonyl stretching with the
vacuum field (zero-point energy of the cavity) has been realized;
this is also known as vacuum Rabi splitting.[7]
clearly depends on the degree of resonance, with the rate of
reaction as a function of cavity mode energy (red dots) being
well-superimposable on the shape of carbonyl stretching
vibration band (black line) in Fig. 3. When the cavity mode was
adjusted to match the maximum of the carbonyl stretch, the
reaction rate was decreased by 70% compared to the
completely detuned case.
The magnitude of vacuum Rabi splitting is proportional to
the square root of the concentration of acetaldehyde (Fig. S2),
as predicted in light-matter strong coupling theory.[20,21]
Furthermore, the angle-dependent transmission spectra show a
typical signature of strong coupling: dispersion of both the upper
and lower polariton branches with an anti-crossing at the bare
absorption energy[22] (Fig. S3). These results strongly indicate
that the carbonyl stretching vibration of acetaldehyde in the FP
cavity is exhibiting vacuum Rabi splitting. Strong coupling of the
carbonyls of propionaldehyde, acetone and cyclohexanone were
also confirmed by the square root dependence of their
concentration on the observed Rabi splitting[7] (Figs. S4-6).
We carried out the Prins cyclization of acetaldehyde
propionaldehyde, acetone, or cyclohexanone with 3-butene-1-ol
in FP cavites under two conditions for each reaction, namely,
with the cavity mode strongly coupled to (ON-resonance), or
detuned from (OFF-resonance), the carbonyl groups. The
reaction conditions (see Experimental section) were determined
based on those typical for a bulk reaction in the presence of
iodine (Fig. S7). This reaction mechanism is described in the
Supporting Information (Fig. S8). As the reaction proceeds, the
refractive index of the solution in FP cavity slightly increased in
both ON- and OFF-resonance cases. The increase of the
refractive index of the solution as the reaction progressed
induced a shift of the resonant peak wavenumber (v) of the
progression of higher order, non-resonant FP cavity modes from
νinitial to νt. These shifts allowed the kinetics of the Prins
cyclization to be monitored by transmission spectroscopy[11]
(Figs. 2b-c). The plot of (1 - c (ν0 - νt)/(ν0 - ν )) against time
Figure 2. (a) IR transmission spectra of 50 vol% acetaldehyde in
dichloromethane (black) and pure dichloromethane (blue). Vibro-polatironic
states P+ and P- formed by coupling of the 6th order cavity mode with
carbonyl stretching vibration (red). The vertical axis on the left is for the cavity
peaks (red); the vertical axis on the right is for 50 vol% acetaldehyde in
dichloromethane (black) and pure dichloromethane (blue). (b-c) The temporal
shift of the higher-order cavity modes: (b) on-resonance and (c) off-resonance.
Each color indicate the cavity peak at a certain reaction time: orange (0 min),
green (5 min), blue (10 min), purple (15 min), magenda (20 min) and yellow
(25 min). (d) Kinetics of the reactions in the FP cavities tuned to be on-
resonance (red filled circle) and off-resonance (red open circles), as extracted
from the temporal shifts in the higher-order cavity modes.
∞
∞
gave a straight line, indicating the Prins cyclization was a
second-order reaction (Fig. 2d and Figs. S9). The observed
second-order kinetics of the Prins cyclization agrees with the
reaction mechanism described in the literature,[19] namely
second-order reaction (Fig. S10). In all the cases (acetaldehyde,
propionaldehyde, acetone, and cyclohexanone), the change of
the refractive indices under on-resonance conditions was slower
than under off-resonance conditions (Fig. 2d). This suggests that
VSC of the carbonyl stretching vibration of the aldehyde and
ketone decreased the reactivity of the substrate in a Prins
cyclization.
The reaction rate was quantitatively determined by gas
chromatography-mass spectrometry (GC-MS) to monitor the
decrease of the 3-butene-1-ol starting material. To confirm the
effect of VSC on the reaction kinetics, the wavelength of the
cavity mode was scanned around the carbonyl stretching
vibration energy and the reaction repeated. The effect of VSC
The reaction rates under On-resonance and Off-resonance
conditions were also measured at different temperatures (22 °C,
30 °C and 40 °C, Fig. S11 and Table S2). At all the
temperatures, the reaction rates of Prins cyclization was
decreased by VSC of the carbonyl stretching vibration. The
enthalpy and entropy of activation of the Prins cyclization under
on- and off-resonance were estimated by Eyring plots (Fig. S12
and Table 1. Although aldehydes are more reactive than
ketones in Prins cyclization because of the increased polarity of
the carbonyl groups of the former, the activation enthalpy (ΔH‡)
of the Prins cyclization of all reactants increased by
approximately 10 kJ/mol under VSC (ca. 1.5-fold increase);
however, the activation entropy (ΔS‡) was not altered as much
(ca. 10% less negative). The activation enthalpy of all the
reactions under ON- and OFF-resonance conditions was plotted
against activation entropy (Fig. S13). The linear correlation
This article is protected by copyright. All rights reserved.

10.1002/anie.201915632
Angewandte Chemie International Edition
COMMUNICATION
between Δ H‡ and Δ S‡ implies that all the aldehydes and
ketones react by the same mechanistic pathway when subjected
to carbonyl VSC, but with the energy barrier to reaction
increased. The rate-limiting step in the Prins cyclization is the
attack by the alcohol group of 3-butene-1-ol at the carbonyl
group and protonation of the carbonyl group, which is facilitated
by the latter’s polarity. The increase of the activation energy by
VSC observed here might suggest that the effect of VSC on the
carbonyl stretching vibration is akin to decreasing the polarity of
the carbonyl group.
1.1 × 10-4
2.5 × 10-5
1.1 × 10-4
3.1 × 10-5
7.4 × 10-5
1.4 × 10-5
OFF-resonance
ON-resonance
OFF-resonance
ON-resonance
OFF-resonance
ON-resonance
propionaldehyde]
Acetone
cyclohexanone
Table 2. Activation enthalpy, entropy and energies of aldehydes and ketones
under On- and OFF- resonance.
[c]
ΔH‡ [a]
ΔS‡ [b]
Ea
Reactant
state
(kJ/mol)
(J/mol•K)
(kJ/mol)
19.2
30.9
23.4
37.6
25.0
36.8
27.1
38.8
-251.1
-222.7
-240.7
-204.7
-236.5
-209.9
-231.7
-205.6
21.8
33.5
26.0
40.1
27.5
39.4
29.6
41.3
OFF-resonance
ON-resonance
OFF-resonance
ON-resonance
OFF-resonance
ON-resonance
OFF-resonance
ON-resonance
Acetaldehyde
propionaldehyde]
Acetone
cyclohexanone
[a] Activation enthalpy, [b] activation entropy and [c] activation energy
estimated by Arrhenius plot
While broadly attributed to the re-shaping of the reaction
potential energy landscape by hybrid light-matter states, a clear
picture of the effect of VSC on organic chemistry is still lacking.
Nevertheless the results presented here add new insights and
hint at trends which may help interpret the four reports published
so far in this field.[7-11] The deprotection of silyl groups slows
down under VSC of the Si-C vibration, correlating with the
slowing down of cyclization observed here. The rate-limiting step
of silyl deprotection is the attack of an alcohol at the Si center,
so one could again speculate that decreasing the polarity of Si-C
bond would decrease the rate of the deprotection reaction.[10,11]
However in that work VSC lead to a large increase in activation
entropy indicating a change from an associative to a dissociative
transition state, something not observed here for Prins
cyclization. While we speculate that VSC of the reactants gives
an effect similar to that of decreasing the polarity of functional
groups coupled to the cavity mode, other works focusing on
cooperative VSC of solvents and reactants reveal contrary
trends.[12–14] For the solvolysis of para-nitrophenyl acetate for
example, the reaction rate increases, the activation entropy
decreases, and a more polar activated complex is invoked.
Indeed while a global (and predictive) model for the effect of
VSC on reactions rates would be intellectually pleasing, it may
turn out that the minutiae of each specific reaction dominates.
Figure 3. (a) The reaction rate as a function of the FP cavity tuning for
reactions occurring within (red dots). The solid black line shows the IR
transmission spectrum of the carbonyl stretching vibration of acetaldehyde. (b)
Eyring plot of the Prins cyclization of acetaldehyde. The circles and dots
indicate off-resonance, and on-resonance, respectively.
Table 1. Reaction rates of the Prins Cyclization at 22 °C
kobsd
Reactant
state
(mol/L•s)
1.8 × 10-4
4.7 × 10-5
OFF-resonance
ON-resonance
Acetaldehyde
This article is protected by copyright. All rights reserved.

10.1002/anie.201915632
Angewandte Chemie International Edition
COMMUNICATION
[9]
J. Flick, M. Ruggenthaler, H. Appel, A. Rubio, Proc. Natl. Acad. Sci.
U. S. A. 2017, 114, 3026–3034.
[10]
A. Thomas, J. George, A. Shalabney, M. Dryzhakov, S. J. Varma, J.
Moran, T. Chervy, X. Zhong, E. Devaux, C. Genet, et al., Angew.
Chemie - Int. Ed. 2016, 55, 11462–11466.
[11]
A. Thomas, L. Lethuillier-Karl, K. Nagarajan, R. M. A. Vergauwe, J.
George, T. Chervy, A. Shalabney, E. Devaux, C. Genet, J. Moran,
et al., Science 2019, 363, 615–619.
[12]
[13]
H. Hiura, A. Shalabney, J. George, Chemrxiv.Org 2018.
J. Lather, P. Bhatt, A. Thomas, T. W. Ebbesen, J. George, Angew.
Chemie Int. Ed. 2019, 58, 10635–10638.
[14]
R. Vergauwe, A. Thomas, K. Nagarajan, J. George, T. Chervy, M.
Seidel, E. Devaux, V. Torbeev, T. W. Ebbesen, Angew. Chemie Int.
Ed. 2019, 58, 15324–15328.
[15]
[16]
[17]
[18]
[19]
[20]
J. S. Yadav, B. V Subba Reddy, V. H. Krishna, T. Swamy, G. K.
Narayana Kumar, Can. J. Chem. 2007, 85, 412–415.
X. Gang, Y. Zhu, H. Birch, H. A. Hjuler, N. J. Bjerrum, Appl. Catal. A
Gen. 2004, 261, 91–98.
Figure 4. The activation enthalpy (ΔH‡) is plotted against the activation
entropy (ΔS‡). Red, orange, green and blue indicate acetaldehyde,
propionaldehyde, acetone, and cyclohexanone, respectively. The circles and
dots indicate off-resonance, and on-resonance, respectively.
G. Sabitha, K. B. Reddy, M. Bhikshapathi, J. S. Yadav, Tetrahedron
Lett. 2006, 47, 2807–2810.
L. J. Dolby, C. L. Wilkins, R. M. Rodia, J. Org. Chem. 1968, 33,
4155–4158.
In summary, we investigated the effect of VSC on a series
of carbonyl reactants undergoing a Prins cyclization. Under VSC
the reaction rate was significantly decreased in all cases without
K. B. Schowen, E. E. Smissman, R. L. Schowen, J. Org. Chem.
1968, 33, 1873–1876.
R. M. A. Vergauwe, J. George, T. Chervy, J. A. Hutchison, A.
Shalabney, V. Y. Torbeev, T. W. Ebbesen, J. Phys. Chem. Lett.
2016, 7, 4159–4164.
evidence of
a
change in mechanistic pathway. This
comprehensive work on a series of aldehydes and ketones
suggests that VSC has an effect similar to that of weakening the
polarity of carbonyl groups. This is the first example of VSC-
induced control of a nucleophilic reaction and it suggests that
VSC may have wide application because nucleophilic attack is a
feature of a vast number of organic reactions.
[21]
[22]
B. S. Simpkins, K. P. Fears, W. J. Dressick, B. T. Spann, A. D.
Dunkelberger, J. C. Owrutsky, ACS Photonics 2015, 2, 1460–1467.
J. George, T. Chervy, A. Shalabney, E. Devaux, H. Hiura, C. Genet,
T. W. Ebbesen, Phys. Rev. Lett. 2016, 117, 153601.
Acknowledgements
This work was supported by JST PRESTO (JPMJPR18TA)
and JSPS KAKENHI (Grant Nos. JP18K19085) and, and
partially supported by JSPS Core-to-Core Program A. Advanced
Research Networks.
Keywords: Rabi splitting • vibrational strong coupling • Prins
cyclization• infrared spectroscopy•microcavity
[1]
[2]
[3]
R. Houdré, R. P. Stanley, M. Ilegems, Phys. Rev. A - At. Mol. Opt.
Phys. 1996, 53, 2711–2715.
J. Casanova, G. Romero, I. Lizuain, J. J. García-Ripoll, E. Solano,
Phys. Rev. Lett. 2010, 105, 263603.
R. M. A. Vergauwe, J. George, T. Chervy, J. A. Hutchison, A.
Shalabney, V. Y. Torbeev, T. W. Ebbesen, J. Phys. Chem. Lett.
2016, 7, 4159
[4]
[5]
M. Hertzog, M. Wang, J. Mony, K. Börjesson, Chem. Soc. Rev.
2019, 48, 937
R. Damari, O. Weinberg, D. Krotkov, N. Demina, K. Akulov, A.
Golombek, T. Schwartz, S. Fleischer, Nat. Commun. 2019, 10,
3248.
[6]
[7]
[8]
J. P. Long, B. S. Simpkins, ACS Photonics 2015, 2, 130–136.
T. W. Ebbesen, Acc. Chem. Res. 2016, 49, 2403–2412.
F. Herrera, F. C. Spano, Phys. Rev. Lett. 2016, 116, 1–6.
This article is protected by copyright. All rights reserved.

10.1002/anie.201915632
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Layout 1:
COMMUNICATION
Vibrational strong coupling (VSC) of
a series of aldehyde and ketone
reactants in Prins cyclization is
investigated. The second-order rate
constant is decreased by VSC of the
carbonyl stretching band. The
extension of VSC chemistry to
common cycloadditions further
establishes a link between quantum
electrodynamics and synthetic
chemistry.
Kenji Hirai,* Rie Takeda, James A.
Hutchison, and Hiroshi Uji-i*
Page No. – Page No.
Modulation of Prins Cyclization by
Vibrational Strong Coupling
This article is protected by copyright. All rights reserved.