A concerted addition mechanism in [Hmim]Br-triggered thiol-ene reactions: a typical “ionic liquid effect” revealed by DFT and experimental studies

Article abstract of DOI:10.1039/c8nj05674a

A concerted one-step addition mechanism for anti-Markovnikov hydrothiolation in [Hmim]Br catalyzed thiol-ene reactions is revealed by a combined DFT and experimental study for the first time. This special mechanism represents a typical “ionic liquid effec

Full text of DOI:10.1039/c8nj05674a

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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A Concerted Addition Mechanism in [Hmim]Br-Triggered Thiol-
Ene Reactions: A Typical “Ionic Liquid Effect” Revealed by DFT and
Experimental Studies
Received 00th January 20xx,
Accepted 00th January 20xx
Lin Feng+, Renlong Ye+, Tao Yuan, Xiao Zhang, Guo-ping Lu* and Baojing Zhou*
DOI: 10.1039/x0xx00000x
A concerted one-step addition mechanism for the anti-Markovnikov hydrothiolation in [hmim]Br catalyzed thiol-ene
reactions is revealed by a combined DFT and experimental study for the first time. This special mechanism represents a
typical “ionic liquid effect”, which is driven by the directional hydrogen bond and π+-π interactions that conjoin the
substrates and [hmim]Br to a prereactive complex. The transition state is stabilized and characterized by a planar 6-
membered ring containing HBr and four substrate atoms at the reaction site. The concerted addition mechanism and the
special structural feature of the TS renders the reaction regiospecific, i.e. only the anti-Markovnikov product is produced.
When the styrene is replaced by aliphatic alkenes, the substrates are loosely bound with the ionic liquid. As a result, the
prereactive complex is destabilized and the reactivity drops significantly.
www.rsc.org/
medicine owing to its high atom economy, simple synthetic
procedures and minimum waste generation.10 Thiol-ene
additions can be promoted through different ways, such as
through free radicals11, strong acids or bases12 and metal
catalysts13. In these conditions, the control of the stereo- and
regioselectivity still remains an important challenge. As an
Introduction
Although the environmental fate of ILs is a complex
situation, and the number of synthesis steps for ILs seems
likely to be more than that of several other common organic
solvents,1 ionic liquids (ILs) have several unique properties,2
such as self-assemble, negligible vapor pressure, non-
flammability and outstanding solvation potential. All of these
properties offer considerable applications of ILs including
organic synthesis, catalysis, chemical separation, material and
energy science.3 The non-covalent interactions, including the
electrostatic interaction, hydrogen bonding4 and dispersion
interaction, play a crucial and complex role in ILs being
developed for practical applications. These include the ability
of ILs to dissolve recalcitrant materials5 and to serve as
extraction and separation media.6 More recently, the ILs have
been proven to benefit some transformations and influence or
even change the mechanisms of some reactions through these
non-covalent interactions.7 The unusal solvation behaviors of
the ILs are further coined as the “ionic liquid effect”.8 However,
researches on the reaction mechanisms impacted by ILs as the
solvents are still limited9 and more insights are required to
fully understand the “ionic liquid effect” at the molecular level.
Thiol-ene chemistry has emerged as a powerful strategy to
construct carbon-sulfur bonds, which is widely applied in the
fields of nanoengineering, polymer science, biology and
alternative, thiol-ene reactions in ILs provide
a great
opportunity to explore the mechanisms of thiol-ene reactions
in ionic environment and represent the intersection of two
important yet diverse fields. Based on a series of experiments
including MS, NMR, and control experiments, Sinha et al.
proposed a tentative mechanism for the thiol-ene reaction in
1-hexyl-3-methylimidazolium bromide ([hmim]Br), in which
the C-2 hydrogen of the imidazolium cation interacts with 4-
methylstyrene (electrophilic activation) and the Br anion
interacts with the S-H of thiophenol (nucleophilic activation)
via H-bond formations (Scheme 1a).7g
a.Chemical Engineering College, Nanjing University of Science & Technology
Xiaolingwei 200, Nanjing, 210094 (China)
Scheme 1 Comparison of the proposed mechanisms for the thiol-styrene reaction
catalyzed by [hmim]Br.
* Corresponding authors, email: glu@njust.edu.cn; bzhou@njust.edu.cn
+ These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [More details for
experiments and DFT studies]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Despite the plausibility of such a mechanism, several for such a reaction channel is only 20.9 kcal/mol (Fig. 1), much
problems remain unresolved concerning its accuracy. First and lower than that of the Br-mediated channel. This is mainly
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DOI: 10.1039/C8NJ05674A
foremost, the interaction between IL, styrene and thiol attributed to the formation of a 6-membered ring at the
remains vague, in particular the orientation of the hmim cation reaction site of the TS. Another advantage for the HBr-
in the prereactive complex. The formation of the prereactive meditated channel is the extra stability of the product complex
complexes is of vital importance for organic reactions.14 In (-7.5 kcal/mol, Fig. 1).
contrast to van der Waals complexes, which fall apart
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reversibly into their constituents, weakly bounded prereactive
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complexes are complexes can precede the activation barrier
along the reaction path.14a It was suggested that the C-2
hydrogen of hmim cation interacts with the vinyl of styrene
(Scheme 1a). However, as demonstrated by our density
functional theory (DFT) calculations, the acidic C-2 hydrogen
prefers to point toward the more electron-rich benzene ring of
styrene. Second, how does the hydrogen transfer to the α-C of
styrene in the hydrothiolation process? Furthermore, does the
anti-Markovnikov addition proceed in a stepwise manner or in
a concerted style? It is a primary problem whether the
chemical reaction is carried out through stepwise or concerted
mechanism in the study of organic chemical mechanism. From
a theoretical point of view, the answer is related to our
fundamental understanding of the reaction; from the
application point of view, the reaction pathway also directly
affects the stereoselectivity, solvent effect, product
distribution, etc.15 Further studies are necessary for obtaining
an in-depth understanding of these fundemantal problems
arising from the hydrothiolation reactions in [hmim]Br. Based
on DFT calculations and control experiments, herein we
propose a novel mechanism for the thiol-ene reactions in ILs
(Scheme 1b), which represents a typical “ionic liquid effect”.
Such a mechanism features the concerted hydrothiolation and
leads to further experimental discoveries, i.e. the reactivity of
this type of reaction declines significantly for aliphatic alkenes
mainly due to the weakened interactions between the IL and
ene substrate.
Fig. 1. Free energy (kcal/mol) profiles along the reaction coordinates: comparison of
the Br-mediated reaction channel (blue line) and HBr-mediated reaction channel (red
line) of thiol-styrene reaction.
The HBr-mediated reaction channel is also supported by the
experimental results. First, in the ESI-MS data from Sinha’s
work (Fig. S1-S3 in SI7g), the total ion chromatogram (TIC)
revealed the presence of ions at m/z 493, 413 and 379, which
may corresponds to [RC2+NH3]+, [RC2+NH3-Br]+ and [RC2+NH3-
Br-CH3]+, which is a positive evidence for the existence of the
prereactive complex (RC2 in Fig. 1) presented in the HBr-
mediated channel. In addition, in our control experiments,
when adding a base (NaOH) into the reaction system, the
reaction yield drops significantly from 87% to 19% (Table S1,
entries 1 vs. 2). This is consistent with the fact that the
Results and discussion
For the thiol-styrene reaction in [hmim]Br, one may addition of the base nullifies the formation of HBr and thus
speculate that the S-H proton transfers directly to the α-C of disrupts the HBr-mediated reaction channel. Hence, the HBr-
vinyl group, in concerted with the formation of the C-S bond to mediated reaction channel should be the main pathway for
yield the final product. In this case, the Br anion not only hydrothiolation of styrene in [hmim]Br.
weakens the original S-H bond, but also mediates the proton
The structures of the reactant, TS, product and reaction
transfer from S atom to the α-C. We refer to this reaction path of the HBr-mediated reaction channel are illustrated in
pathway as the Br-mediated reaction channel and a reaction Fig. 2. In the prereactive complex (Fig. 2a), the positively
barrier of 34.4 kcal/mol was predicted by DFT calculations (Fig. charged imidazolium ring (π+ ring) of hmim cation is almost
1; see Section 2.1 of the Supporting Information (SI) for more perpendicularly above the styrene with the C-2 H pointing to
details). The high barrier of the Br-mediated reaction channel the benzene ring (π ring), establishing the T-shaped π+-π
is mainly due to the unstable transition state (TS), in which a 4- interactions.4b, 4c, 16 Two H-bonds are identified, one between
membered ring of large strain is formed at the reaction site.On the HBr hydrogen and the vinyl and another between the S-H
the other hand, the Br anion can be protonated to form the of thiophenol and bromine with lengths ca. 2.5 Å 4a
HBr molecule as a result of the acid-base dissociation of the (Fig. 2b), the distance between the proton and α-C is
thiol in IL or the proton exchange of IL (Scheme S1 in SI).8b We significantly reduced (ca. 1.78
), while the S, Br, α-C, β-C and
. In the TS
Å
refer to this mechanism, in which the HBr serves as the acid- two H atoms at the reaction site form a planar pentagonal 6-
catalyst and the hydrothiolation proceeds via the proton membered ring. Such a unique transition state (TS) determines
transmission, as the HBr-mediated reaction channel (Fig. 1).As the most important feature of this reaction, i.e. the
revealed by DFT computations, the free energy of activation protonation of the α-C occurs concertedly with the formation
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of the C-S bond. Consequently, the reaction is regiospecific and of [hmmim]Br based on the HBr-mediated channel. The
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only anti-Markovnikov product is yielded. Conversely, for the resulting reaction barrier of 22.5 kcaDl/OmI:o1l0.1(0F3ig9./C83N)J0is56714.6A
conventional stepwise Markovnikov17 mechanism or anti- kcal/mol higher than that for [hmim]Br (Fig. 1). In addition, the
18
Markovnikov10d,
mechanism, regioselectivity is usually relative stability of the product compared to the prereactive
exhibited. In the product complex, the styrene is complex is only -5.9 kcal/mol, while for [hmim]Br, it is -7.5
hydrothiolated and the catalytic HBr is recovered (Fig. 2c). kcal/mol. Thus, the methylation at the C-2 position of [hmmim]
Throughout the reaction, the hmim cation is situated above cation interrupts its π+-π interaction with styrene, which
the styrene with its C-2 H pointing to the benzene ring of lowers the stability of the both the TS and product.
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styrene.
If the π+-π interactions between the styrene and hmim
cation is essential for the high catalytic efficiency of the latter
in this reaction, for aliphatic alkenes, the lack of π+-π
interactions should severely lower the reactivity. We screened
four different alkenes including styrene, 1-octene, 2-
vinylpyridine and 3-(4-methoxyl-phenyl)propene in thiol-ene
reactions. Their reaction rates are compared in Fig. 4. As
expected, the styrene and 2-vinylpyridine are highly reactive,
while 3-(4-methoxyl-phenyl)propene exhibits low reactivity,
and 1-octene is almost inactive.
Fig. 2. Geometries of the prereactive complex (a), transition state (b) and product
complex (c), as well as the bond cleavages and formations along the IRC path (d) of
thiol-styrene reaction in [hmim]Br
The free energy profile of this reaction contains no
intermediate (Fig. 1) due to its concerted addition mechanism.
As shown in Fig. 2d, along the IRC path,19 near the TS, the H-Br
bond breaks (blue curve) and the new C-H bond forms (red
curve) simultaneously and both display rapid changes, which
precedents the cleavage of the S-H bond (black curve) and the
formation of the C-S bond (violet curve).
Fig. 4. The comparison of the reaction rates of four alkenes. Conditions: alkenes 0.50
mmol, 4-methylthiophenol 0.55 mmol, [hmim]Br 1 mL, 40 oC or 80 oC; GC yields. i) 2-
vinylpyridine, 40 oC. ii) styrene, 40 oC. iii) 3-(4-methoxyl-phenyl)propene, 80 oC. iv) 1-
octene, 80 oC.
From DFT computations, the reaction barriers for the four
alkenes increase in the following order: 3-(4-methoxyl-
phenyl)propene (17.8kcal/mol) < 1-octene = 2-vinylpyridine
(18.0 kcal/mol) < styrene (20.0 kcal/mol) (see Fig. S3 of the SI).
A similar trend is also observed in the free energy changes
when the prereactive complexes are converted to the products
(see Fig. S3 of the SI). Clearly, these computational results are
not in accord with the experimental results.
Since the stability of the prereactive complex plays a key
role in chemical reactions,20 the stabilities of the prereactive
complexes for the aforementioned systems were examined to
rationalize the measured reaction rates. We computed the
binding affinities of the prereactive complex by
supramolecular approach as following (Table. 1)21
Δ퐺푏ꢀ푛푑 = 퐺푅퐶 − 퐺푒푛푒 − 퐺푡ℎꢀ표푙 − 퐺ℎ푚ꢀ푚−퐻퐵푟 (1)
a
Fig. 3. The free energy profile (kcal/mol) and geometries of prereactive complex,
transition structure and product complex of the thiol-styrene reaction in [hmmim]Br.
Here G denotes the Gibbs free energy and the prereactive
complex (RC) is partitioned into three components: the ene,
thiol, and IL.
As judged by the computed binding affinities, the stabilities
of the four prereactive complexes decrease in the following
order: 2-vinylpyridine ≈ styrene > 1-octene ≈ 3-(4-methoxyl-
phenyl)propene. For styrene and 2-vinylpyridine, their
Methylation at the C-2 position of the imidazolium ring
considerably lowers the catalytic efficiency of the IL in thiol-
ene reactions.7f,
experiments by the reaction yields: 87% in [hmim]Br vs. 62% in
[hmmim]Br (Table S1, entries 1 vs. 3). We further performed
DFT computations to examine the origin of catalytic deficiency
7g
This is also verified in our control
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prereactive complex show much stronger stabilities than those hmim cation further destabilizes the prereactive complex. The
of 3-(4-methoxyl-phenyl)propene and 1-octene and the poor stabilities of prereactive complex eventually lead to the
difference in binding affinities is over 2 kca/mol (see Table 1). overall drop of reactivity of the aliphatic alkenes. Moreover,
Thus, for 1-octene and 3-(4-methoxyl-phenyl)propene, it is we find that the IL cation is also capable of CH-π interactions
more difficult for the various ingredients to assemble together, with C=C double bond of 1-octene by comparing the stability
which leads to a low orientation factor in the Arrenius of two different conformations formed by 1-octene and IL
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DOI: 10.1039/C8NJ05674A
equation.
cation (see Fig. S5 of the SI). The interactions will cause one
face of 1-octene to be hindered for the reaction with
thiophenol and eventually lead to the lower rates of 1-octene.
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Table 1. The binding affinities of prereactive complexes as well as their enthalpy,
entropy and solvation free energy components (kcal/mol).
Alkenes
styrene
ΔH
-TΔS
25.2
25.2
26.7
ΔG푣푎푐푢
0.9
ΔG푠표푙푣
12.4
Δ퐺푏ꢀ푛푑
13.2
Experimental
Computational Methods
-24.3
-25.9
-22.4
The multicoordinate driven (MCD) method22 was employed
to drive the reaction system from the prereactive complex to
the product, which yielded the initial guesses of transition
states (TSs). These initial guesses were further optimized to
the true TSs. Geometry optimizations of the prereactive
complex, TSs and product complexes were performed at the
B3LYP/6-31+G(d,p) level23 incorporating the Grimme’s D3(BJ)24
approach for dispersion corrections. The frequency
calculations were performed at the same level to verify the
stationary point nature of the optimized structures and to
obtain the thermal corrections to the Gibbs free energies. The
prereactive complex and product complexes were
characterized by all positive vibrational frequencies, indicating
that they were true minima. The TSs were validated by a single
imaginary (negative) vibrational frequency for the saddle point
nature and by intrinsic reaction coordinate (IRC)19
computations for the correct connections to the reactants and
products. All of the geometry optimizations and frequency
calculations were performed in the gas phase. The gas-phase
single point energy of the optimized structure was further
refined at B3LYP-D3(BJ)/def2-QZVP25 level, which was added
to the thermal corrections computed at B3LYP-D3(BJ)/6-
31+G(d,p) level to obtain the Gibbs free energy in vacuum,
2-
vinylpyridin
e
-0.6
13.5
12.9
1-octene
4.3
10.9
15.2
3-(4-
methoxyl-
phenyl)pro
pene
-28.2
28.0
-0.2
15.8
15.6
퐺푣푎푐푢 = 퐻 − 푇푆
The reported Gibbs free energy,
energy in vacuum and the solvation effect,
Δ퐺 = Δ퐺푣푎푐푢 + Δ퐺푠표푙푣
where the second term on the right were computed from the
.
(1)
퐺
, includes the Gibbs free
Fig. 5. The prereactive complexes of thiol-ene reactions involving four alkenes: (a)
styrene, (b) 2-vinylpyridine, (c) 3-(4-methoxyl-phenyl)propene and (d) 1-octene.
,
(2)
We further compare the structures of the four prereactive continuum solvent model. The optimized structures in the gas
complexes in Fig. 5. The π ring of the styrene facilitates the π+- phase were used and the solvation free energies were
π interactions with hmim cation (panel a), whereas the N atom computed at the M06-2X/6-31G(d,p) level26 employing the
of π ring of 2-vinylpyridine undergoes strong interactions with SMD-generic ionic liquid (SMD-GIL)27 solvation model. The
the C-2 H of hmim cation (panel b). The overall structures of solvent descriptors of [hmim]Br and [hmmim]HBr used in
their prereactive complex are well-ordered. In contrast, for 3- SMD-GIL solvation model are listed in Table S4 of the SI. The
(4-methoxyl-phenyl)propene (panel c) and 1-octene (panel d), [hmim]Br and [hmmim]HBr share the same set of generic
their vinyl groups gain the rotational freedom due to the parameters except Carbon Aromaticity and Electronegative
absence of the conjugated π ring, which can be proved by the Halogenicity, which depend solely on the molecular structure
dihedral scan of 3-(4-methoxyl-phenyl)propene (see Fig. S4 of of the IL. All of the Gibbs free energies were computed at
the SI). The relative orientation between the vinyl, HBr and 298.15 K and 1 atm. All DFT calculations were performed with
thiol becomes distorted, which impedes the directional and Gaussian 09 package.28 The GRRM program interfaced with
consecutive H-bond interactions between the vinyl, HBr and S- Gaussian 09 was employed to pre-optimize the geometry to
H. As a result, the clustering of the substrates is severely facilitate the convergence.29
wakened. For 1-octene, the lack of π+-π interactions with
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Experimental methods
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Petkovic, K. R. Seddon, L. P. Rebelo andDCO.I:S1i0lv.1a0P39e/rCe8irNaJ,0C5h6e7m4A.
Soc. Rev., 2011, 40, 1383-1403; (c) M. Amde, J. F. Liu and L.
Pang, Environ. Sci. Technol., 2015, 49, 12611-12627.
General remarks of the experiments: All chemical reagents
were obtained from commercial suppliers and used without
further purification. Analytical thin-layer chromatography was
performed on glass plates precoated with silica gel 2. (a) F. Gayet, J. D. Marty, A. Brulet and N. Lauth-de Viguerie,
impregnated with a fluorescence indicator (254 nm). GC
analyses were recorded on a Hewlett-Packard HP 6890
chromatograph equipped with a capillary column HP-1 (30 m ×
0.25 mm × 0.25 µm). Retention times (tR) refer to the following
temperature program: 70 °C for 0 min; heating rate 20 °C/min;
280°C for 8.50 min; injection temperature 200 °C; detection
temperature 290 °C. 1H NMR spectra are recorded on an
AVANCE 500 Bruker spectrometer operating at 500 MHz in 3. (a) P. C. Marr and A. C. Marr, Green Chem., 2016, 18, 105-128;
CDCl3, respectively, and chemical shifts are reported in ppm.
General procedures for the thiol-ene click reaction in ionic
Langmuir, 2011, 27, 9706-9710; (b) T. L. Greaves and C. J.
Drummond, Chem. Soc. Rev., 2013, 42, 1096-1120; (c) K. L.
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liquids:
A
mixture of alkene 0.50 mmol and 4-
methylthiophenol 0.55 mmol was added in ionic liquids (1 mL),
o
o
which was stirred at 40 C or 80 C as shown in Fig. 4 for 2 h.
Upon completion, the reaction mixture was extracted by
methyl tert-butyl ether (MTBE) (3×2 mL). The organic phase
was collected and filtered through a bed of silica gel layered
over Celite. The volatiles were removed in vacuo to afford the
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Conclusions
In summary, we disclose a concerted one-step addition
mechanism promoted by the π+-π and H-bond interactions
between [hmim]Br and substrates in the thiol-ene reactions,
which represents a typical “ionic liquid effect”. Based on this
mechanism, we rationalize the catalytic deficiency of
[hmmim]Br and predict the low reactivity of aliphatic alkenes
in such reactions. A high quality IL catalyst should not only
stabilize the transition state but also efficiently facilitate the
formation of the stable prereactive complex. This chemistry
introduces
a new mechanism for the anti-Markovnikov
hydrothiolation as well as offers new insight into the roles of
ILs in organic transformation.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge for the Chinese Postdoctoral
Science Foundation (2015M571761, 2016T90465). We think
Lan Yi at Test Center Nanjing University of Science and
Technology for the help in obtaining the NMR data.
Notes and references
This journal is © The Royal Society of Chemistry 20xx
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The π+-π and H-bond interactions between [hmim]Br and substrates promote a special
one-step addition mechanism in thiol-ene reactions.