Reaction evolution of a solvate fluoride ionic liquid induced fluorination process probed by Raman spectroscopy

Article abstract of DOI:10.1016/j.molliq.2020.112819

Currently, about 30% of new approved drugs contained fluorine atoms and most of them are made through fluorination reactions using various kinds of fluorinating reagents. In the current work, we report a facile and more accessible way to probe the fluorination evolution at different stages using a newly developed fluorinating reagent (1-ethyl-3-methylimmidazolium fluoride-ethylene glycol, [C₂C₁im]F-EG). Benzyl bromide was converted to benzyl fluoride using this fluorinating reagent under mild conditions. A more accessible Raman method, compared to NMR, was used to probe the reaction process due to the products having their own characteristic Raman vibrational frequencies because of the formation of different C-X bonds. Thus the yield of the product at different time scales could be then quantified based on their relative intensities, providing a fresh insight into the fluorination process. This method could be applied in other reactions to reflect the important fluorination process, which methodologically reports a facile way to probe reaction processes.

Full text of DOI:10.1016/j.molliq.2020.112819

Journal of Molecular Liquids 305 (2020) 112819
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Reaction evolution of a solvate fluoride ionic liquid induced fluorination
process probed by Raman spectroscopy
a
a
a
b
b,
Zhengfei Chen a, , Meng Deng , Zhanghua Gao , Zhijiang Jiang , Lichun Li , Haodong Tang
⁎
⁎
a
School of Biological and Chemical Engineering, Ningbo Institute of Technology, Zhejiang University, Ningbo, China
College of Chemical Engineering, Zhejiang University of Technology, 18 Chaowang Rd, Hangzhou, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Currently, about 30% of new approved drugs contained fluorine atoms and most of them are made through fluo-
rination reactions using various kinds of fluorinating reagents. In the current work, we report a facile and more
accessible way to probe the fluorination evolution at different stages using a newly developed fluorinating re-
agent (1-ethyl-3-methylimmidazolium fluoride-ethylene glycol, [C2C1im]F-EG). Benzyl bromide was converted
to benzyl fluoride using this fluorinating reagent under mild conditions. A more accessible Raman method, com-
pared to NMR, was used to probe the reaction process due to the products having their own characteristic Raman
vibrational frequencies because of the formation of different C-X bonds. Thus the yield of the product at different
time scales could be then quantified based on their relative intensities, providing a fresh insight into the fluori-
nation process. This method could be applied in other reactions to reflect the important fluorination process,
which methodologically reports a facile way to probe reaction processes.
Received 22 December 2019
Received in revised form 18 February 2020
Accepted 1 March 2020
Available online 2 March 2020
Keywords:
Ionic liquids
Fluorinating regents
Fluorination
Raman spectroscopy
© 2020 Elsevier B.V. All rights reserved.
1. Introduction
involves hazardous fluorine gas and the yield is usually very low.
Thus, these routes are unviable from a practical application viewpoint.
Fluorination is prevalent in organic synthetic processes, since the in-
troduction of fluorine atom/s into a molecule can subtly or profoundly
change its physicochemical and biological properties without markedly
altering its conformation compared to the nonfluorinated counterpart
[1–6]. Consequently, fluorination has been widely used in a broad
range of applications in organic chemistry, materials science, agricul-
ture, pharmaceutical and medicinal chemistry [2,4]. Currently, about
30% of new approved drugs contained fluorine atoms [7] and most of
them are made through fluorination reactions using various kinds of
fluorinating reagents [2,8–11]. Many types of fluorinating reagents
such as KF, CsF, AgF and AgF2 or tetramethylammonium fluoride are
commonly used for fluorination reactions, however, these reagents are
solid and have very low solubility in organic solvents [2]. Therefore,
high temperature is often required to facilitate the reaction process,
which would potentially impose safety concerns.
High yield fluorination processes require the fluorinating reagent to
have a sufficiently nucleophilic react to the structur/react to the struc-
ture [1,14–16]. “Naked” fluoride ion has great reactivity for fluorination
reactions but it does not exist in water (or other solvents), fluoride is al-
ways hydrated, or closely associated with its cation [17]; if it could be
prepared, liquid phase naked fluoride would be extremely basic and
has great catalytic activity [16–19].
Recently, quaternary ammonium fluorides based on azabicyclo
[2.2.2]octane were reported to have good reactivity of the nucleophilic
fluoride in a fluorination reaction, but these fluorinating agents were
solid at room temperature and were applied in the presence of volatile,
toxic organic solvents (ACN, DMSO, etc.) at high temperature (80 °C)
[19]. In an attempt to develop more applicable fluorinating agents, a
fluoride solvate ionic liquid (1-ethyl-3-methylimmidazolium fluoride-
ethylene glycol was recently reported: [C2C1im]F-EG) in which the fluo-
ride ion is partially solvated by an ethylene glycol molecule [20]. This
room temperature fluoride ionic liquid showed appreciable solubility
in a common organic solvent (DMF) and demonstrated high reactivity
as a fluorinating reagent under mild reaction conditions (room temper-
ature and short reaction time) with and without solvent due to the fluo-
ride being only partially naked, suggesting its great applicability for
general fluorination reactions. However, the reaction evolution as func-
tion of time has not been revealed for this system (neither for other
analogous systems [19]), which is necessary to understand and control
the process in real applications.
The development of electrophilic fluorinating reagents such as 1-
chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-
borate), N-fluorobenzene sulfonimide, N-fluoropyridinium triflate, N-
fluoroquinuclidinium triflate, etc. [12] that can promote fluorination re-
actions at milder conditions has remarkably advanced fluorinated drugs
[2,13]. However, the preparation of these fluorinating reagents usually
⁎
Corresponding authors.
E-mail addresses: zhengfei.chen@nit.zju.edu.cn (Z. Chen), tanghd@zjut.edu.cn
(H. Tang).
https://doi.org/10.1016/j.molliq.2020.112819
0167-7322/© 2020 Elsevier B.V. All rights reserved.

2
Z. Chen et al. / Journal of Molecular Liquids 305 (2020) 112819
In the current work, we report a facile and more accessible way to
[C2C1im]F-EG
probe the fluorination evolution at different stages using Raman spec-
troscopy. The starting chemical (benzyl bromide) and the product (ben-
zyl fluoride) have their own characteristic vibrational frequencies on
the Raman spectra in some regions due to the formation of different
C-X bonds, which were described in details in literature reports via
both experiments [21,22] and theoretical calculations [23]. Thus the
yield of the product at different time scales can be then quantified
based on their relative intensities, providing a fresh insight into the fluo-
rination process.
[C2C1im]-EG:MeOH:Benzyl Br 2h
[C2C1im]F-EG:Benzyl Br 2h
2. Experimental details
2.1. Materials
All non-volatile materials were handled in a drybox under an atmo-
sphere of dry Ar. The starting bromide salt, 1-ethyl-3-
methylimidazolium bromide ([C2C1im]Br) was purchased from Kanto
Chemical Co. Inc. and was dried under vacuum at 50 °C overnight. Dry
ethylene glycol (EG) (Wako Pure Chemicals, water content b30 ppm)
and methanol (Wako Pure Chemicals, water content b10 ppm) were
used without further purification. Silver fluoride (Aldrich, 99% purity)
was further dried under vacuum overnight at 100 °C. Benzyl bromide
(98%) was purchased from Wako Pure Chemicals and used as received.
Benzyl F
2.2. Synthesis of [C2C1im]F∙EG
Benzyl Br
This sample was prepared from a protocol described in our previous
work [20]. In a typical process, 1.913 g of [C2C1im]Br (10.0 mmol) and
1.266 g of AgF (10.0 mmol) were reacted in dry methanol for 30 min,
and 0.637 g of dry EG (10.2 mmol) was added into it. The reaction mix-
ture was stirred for 24 h and the solid precipitate was filtered. The
methanol in the clear filtrate was removed under vacuum overnight at
25 °C and the final vacuum reached around 1 Pa. The final product typ-
ically resulted in a slightly yellow and viscous liquid.
200
400
600
800 1000 1200 1400 1600 1800
Wavenumber / cm-1
Fig. 1. Raman spectra of benzyl bromide, synthesized benzyl fluoride, benzyl bromide and
[C2C1im]F-EG mixed after 2 h, benzyl bromide and [C2C1im]F-EG mixed in methanol after
2 h, and [C2C1im]F-EG. Red arrow: beznyl fluoride; black arrow: benzyl bromide.
2.3. Spectroscopic measurements
19F NMR was conducted on a JNM–ECA600 NMR spectrometer (JEOL
Ltd.) at room temperature. Neat liquid samples were used for the NMR
measurements. A coaxial NMR tube was used with the sample being
placed in the internal tube and the deuterated solvent in between to
eliminate the interaction with the solvent. Raman spectra were ob-
tained by a Bruker MultiRAM Raman spectrometer equipped with a liq-
uid N2-cooled CCD detector and the laser wavelength was 1064 nm.
When the reaction was completed in a drybox, the reactant mixture
was transferred immediately into a shortened NMR glass tube and
was then sealed for Raman measurement.
in Fig. 1. When benzyl bromide was reacted by [C2C1im]F-EG at 1:1.5 M
ratio for 2 h (without solvent) at room temperature, the characteristic
benzyl bromide bands diminished, suggesting that its full conversion
which is consistent with our previous NMR results [20].
However, the addition of methanol (10 equivalent mole of F¯) can
prevent the fluorination reaction from occurring as shown in Fig. 1,
due to the strong solvation between excessive OH groups (from metha-
nol) and F¯. This result shows that methanol can be used to quench the
reaction at any stage, enabling to monitor the fluorination process.
In the spectrum of benzyl fluoride, the broad band at 400 cm−1 is at-
tributed from the characteristic C-C-F bend [21]. This mode (C-C-Br
bend) is lowered to 238 cm−1 for benzyl bromide [22]. However, the
Raman intensity of the C-C-F bend is weak, which is difficult to be
used for high quality quantification. During the reaction process, the in-
termediate products of the fluorination may contain benzyl bromide,
benzyl fluoride and [C2C1im]F-EG, thus the spectra could be quite com-
plicated. From Fig. 1, it is apparent that some of the fluoride or bromide
related bands could be overlapped. To minimise these effects, we only
chose the least interfered peaks which are 1216 cm−1 for fluoride and
1230 cm−1 for bromide to quantify their respective contents. For the
sake of calibration, pure benzyl fluoride and benzyl bromide at various
molar ratios were firstly mixed in methanol (for better mixing) and
their Raman characteristic peaks in the range of 1190–1250 cm−1 are
shown in Fig. 2 (full range spectra are shown in Fig. S1, ESI). We can
deconvolute these slightly overlapped peaks (the deconvolution of
each sample is shown in Fig. S2, ESI) so that their Raman intensities
(peak areas) can be calculated.
2.4. Fluorination reactions
Benzyl bromide and [C2C1im]F∙EG were directly mixed at 1:1.5 M
ratio in a drybox at room temperature at different time intervals prior
to Raman analysis. Dry methanol (10 equivalent mole to F) was used
to quench the reaction at different stages. Samples were analysed for
Raman immediately after the reaction.
3. Results and discussion
The Raman spectra of benzyl bromide and synthesized benzyl fluo-
ride are shown in Fig. 1, which are in good agreement with the experi-
mental data in the literature where the assignments of the Raman peaks
have been made in details [21,22]. From their spectra, the fluoride or
bromide compound has some unique frequency bands which are 400,
618, 1216 and 1589 cm−1 for benzyl fluoride and 238, 608, 1230,
1603 cm−1 for benzyl bromide, respectively, as indicated by the arrows

Z. Chen et al. / Journal of Molecular Liquids 305 (2020) 112819
3
F
Br
60 min
0.1
Br
30 min
0
0.13
0.19
0.25
0.30
0.01
15 min
F
0.37
0.42
0.50
Br
0.63
0.84
5 min
1
1190
1200
1210
1220
1230
1240
1250
1260
Wavenumber / cm-1
3 min
1 min
Fig. 2. Raman spectra of benzyl bromide and synthesized benzyl fluoride at various
fluoride molar fractions in the region between 1190 and 1260 cm−1
.
Fig. 3 shows the relative intensities between benzyl fluoride and
bromide (area 1216 cm−1/area 1230 cm−1) as function of benzyl fluo-
ride molar ratio. It is worth noting that the relative Raman intensity
does not increase linearly with increasing the benzyl fluoride concen-
tration and it, in fact, increases exponentially which can be best de-
scribed by:
1190
1200
1210
1220
1230
1240
1250
Wavenumber / cm-1
Fig. 4. Relative intensities between fluoride and bromide in the region between 1190 and
1260 cm−1 at different reaction times.
y ¼ 0:0768e3:8548x
ð1Þ
decreased with time. After 60 min, the reaction rate reduced signifi-
cantly as only 26% of benzyl bromide retained which was then con-
verted in the last hour. The change in the reaction rate with time
could be rationalised as more OH groups were released with the reac-
tion proceeding since F replaced the Br on benzyl bromide. In other
words, the F¯/OH ratio decreased with time. This is because the released
Br¯ had very weak interactions with EG, which resulted in “free” EG mol-
ecules as reported in the earlier work [20]. Thus, the reactivity of F¯ re-
duces with increased “free” EG during the reactions.
To verify this hypothesis, we increased the F¯/EG molar ratio from 1
to 1.5 and 2 to form [C2C1im]F-1.5EG and [C2C1im]F-2EG, respectively.
Both samples were reacted with benzyl bromide at the same F/Br ratio
(1.5:1) for 5 min and 30 min, respectively. In the Raman spectra
(Fig. S5, ESI) of the mixture of [C2C1im]F-1.5EG and benzyl bromide,
only very little (negligible) amount of benzyl fluoride was produced
after 5 min, and about 24 mol% benzyl fluoride was detected after
where y is the relative intensity and x is the benzyl fluoride molar ratio.
This equation can then be applied to calculate the molar ratios of benzyl
fluoride at different reaction stages in the subsequent section.
The reaction between benzyl bromide and [C2C1im]F-EG (at 1:1.5 M
ratio) was quenched by methanol at 1, 3, 5, 15, 30 and 60 min, respec-
tively, and their spectra are shown in Fig. 4. At 1 min, the benzyl bro-
mide band dominates and its intensity decreases with increasing
reaction time; vice versa, the benzyl fluoride intensity increases with re-
action time as expected. Similar to that of Fig. 2, the deconvolution
(Fig. S3, ESI) of these two peaks in Fig. 4 gives the relative intensities be-
tween fluoride and bromide (Fig. S4, ESI), and then the molar ratios of
benzyl fluoride (or benzyl bromide) can be acquired using Eq. (1). As
can be seen from Fig. 5, benzyl bromide was consumed logarithmically
with reaction time (eq. shown in the figure); and consistently, benzyl
fluoride showed a logarithmic growth (eq. shown in the figure), mean-
ing the fluorination reaction showed a high rate initially and then
0.8
2.5
2
benzyl fluoride: y = 0.1218ln(x) + 0.1444
0.6
0.4
1.5
y = 0.0768e3.8548x
1
benzyl bromide: y = -0.128ln(x) + 0.7662
0.2
0
0.5
0
0
0.2
0.4
0.6
0.8
1
0
20
40
60
Reacꢀon ꢀme (min)
Benzyl fluoride molar raꢀo
Fig. 3. Relative intensities between benzyl fluoride and bromide (area 1216 cm−1/area
1230 cm−1) as function of benzyl fluoride molar ratio. The solid line is the fit to the data.
Fig. 5. Calculated molar ratios of benzyl fluoride and bromide as function of reaction time.
The solid lines are the fits to the data.

4
Z. Chen et al. / Journal of Molecular Liquids 305 (2020) 112819
30 min (calculated from their deconvoluted peaks). This amount is only
44% of that produced for the [C2C1im]F-EG sample for the same reaction
period. When the F¯/EG molar ratio was increased to 2, no benzyl fluo-
ride was detected both at 5 min and 30 min (Fig. S5, ESI).
the support from NSFC (51303156). The authors would also like to
thank Mr. Masayuki Saimura for the help in measuring 19F NMR at Uji
Campus, Kyoto University.
The increased number of EG molecules in the surrounding of the
[C2C1im]F compound can enhance the solvation of the F¯, which was
reflected by the weaker F¯⋯HO interactions as shown in the previous
1H NMR work [20]. In our 19F NMR results (Fig. S6, ESI), the fluorine
chemical shift moves towards upfield with increasing the EG amount
(−112 ppm for 1EG, −123 ppm for 1.5EG and −128 ppm for 2EG), sug-
gesting increased shielding on the fluoride by increased OH groups thus
reducing its reactivity. On the other hand, the fluorine peak also be-
comes broader as the EG amount increases, which may indicate greater
exchange rate between F¯ ions due to weaker interactions. Therefore,
the dominating factor in determining the rate of the fluorination reac-
tion of benzyl bromide is the ratio between F¯/OH which inevitably de-
creases with the reaction proceeding. In order to achieve reasonable
yield and reaction rate, the starting amount of such fluorinating reagent
([C2C1im]F-EG) may be carefully chosen based on the present result.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.molliq.2020.112819.
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CRediT authorship contribution statement
Zhengfei Chen:Conceptualization, Methodology, Investigation,
Writing - original draft.Meng Deng:Data curation, Writing - original
draft.Zhanghua Gao:Writing - review & editing.Zhijiang Jiang:Soft-
ware.Lichun Li:Software, Formal analysis.Haodong Tang:Writing - re-
view & editing.
Declaration of competing interest
The authors declare no competing financial interest.
Acknowledgement
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Z.C. acknowledges the International Fellowship (P17717) from the
Japan Society for the Promotion of Science (JSPS) carried out at Kyoto
University, Japan. The financial supports from the Start-up Fund from
Ningbo Institute of Technology, Zhejiang University (20190709Z0078).
Z.C. and Z.G. thank the Natural Science Fund from Ningbo Science and
Technology Bureau (2019A610016, 2016A610080). M.D. acknowledges
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