Research Article
Cite This: ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

pubs.acs.org/journal/ascecg

Real-Time Spectroscopic Analysis Enabling Quantitative and Safe
Consumption of Fluoroform during Nucleophilic
Triﬂuoromethylation in Flow
Biagia Musio,* Elena Gala,† and Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensﬁeld Road, Cambridge, CB2 1EW, U.K.
S Supporting Information*

ABSTRACT: The productive use of toxic waste materials
derived from industrial processes is one of the main goals ofmodern chemical research to increase sustainability of the largescale production. Here we devise a simple and robust strategy forthe utilization of triﬂuoromethane, obtained in large quantities
from polytetraﬂuoroethylene manufacture, and the conversion ofthis greenhouse gas into valuable ﬂuorinated compounds. The
generation of the triﬂuoromethyl carbanion and its direct andcomplete consumption through trapping with a number ofelectrophiles were achieved by a fully contained ﬂow reactor
setup. The adoption of modern in-line analytical tools, such as
portable Fourier transform infrared and nuclear magnetic resonance devices, allowed the accurate reagent dosing withconsiderable beneﬁts in terms of controlling the environmental impact during this continuous process. The advantages of themethod, with respect to the batch procedure, will be discussed and demonstrated experimentally.
KEYWORDS: Triﬂuoromethylation, Continuous process, In-line analysis, Benchtop NMR, Fluoroform■

chemically eﬃcient. The recent introduction of ﬂow
technologies into modern laboratory practice has enabled theimproved performance of gas−liquid reactions by expediting
the mass transfer between the two phases.25−32 In particular,
membrane-based reactors have been successfully applied toenable the gas−liquid contact, avoiding the occurrence ofbiphasic ﬂow regime, which may lead to less eﬃcient andcontrollable dosing of the gas.33 A few years ago we contributed
to the development of a tube-in-tube reactor for gas−liquid
reactions, consisting of a pair of concentric capillaries in which
the central capillary functions as a gas-permeable membrane(Teﬂon AF-2400).34,35 This system has been applied to several
synthetic programs, exploiting the permeability of Teﬂon AF2400 to a range of gases (carbon monoxide, hydrogen, ozone,
carbon dioxide, oxygen, ammonia, ethylene, and diazomethane).36−42 More importantly, the advent of a number ofinnovative in-line analytical tools has greatly advanced reaction
monitoring and subsequent adjustment of reaction conditions.43−46 In this context, an increasing number of new
applications have been reported on the use of portable ﬂow IR
devices47−50 and benchtop low-ﬁeld NMR equipment,51−56
which greatly enabled real-time monitoring of continuous ﬂow
chemistry.

INTRODUCTION
There is a clear need to develop modern synthetic strategies
which employ renewable starting materials. Furthermore, there
is also a need to convert waste materials derived from certain
industrial processes into valuable synthetic compounds
improving the sustainability of large-scale production.1−3 A
case in point is the industrial manufacture of polytetraﬂuoroethylene (PTFE) which generates very large amounts oftriﬂuoromethane (CF3H) as a byproduct.4 CF3H is listed as apotent greenhouse gas, with a lifetime of 270 years, which is theapproximate amount of time it would take for CF3H
concentration to return to its natural level.5 Its disposal
requires expensive procedures, such as high-temperatureincineration. Consequently, there is interest in the developmentof aﬀordable transformations which utilize CF3H for the direct
generation of useful functional ﬂuorinated compounds,6−12
which are endowed with improved medicinal or physicalchemical properties.13−15 In particular, signiﬁcant advances
have been achieved during the past decade in the developmentof new reagents and general approaches for triﬂuoromethylation, including electrophilic, radical, and nucleophilic reactions.16−24 Among these methods, the use of CF3H for
installing directly the triﬂuoromethyl moiety into an organic
compound remains an appealing approach, in terms of raw
material availability and atom economy. Nevertheless, as agreenhouse gas, CF3H must not be dispersed into theatmosphere. Thus, an accurate determination of CF3H is vital
during the usage of this reagent to make it ecosustainable and© XXXX American Chemical Society

Received: November 1, 2017
Revised: December 1, 2017
Published: December 7, 2017
A

DOI: 10.1021/acssuschemeng.7b04012
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ACS Sustainable Chemistry & Engineeringa cooling device (Polar Bear Plus from Cambridge Reactor
Design). The gas was introduced into the system using the
tube-in-tube reactor, which is reported as a simple and eﬃcientmethod to aﬀord homogeneous solutions of reactive gases in
ﬂow (Figure 1b).
First, it was veriﬁed that the Teﬂon AF-2400 membrane of
the inner tube, containing tetrahydrofuran (THF), waspermeable to CF3H. For this purpose, an in-line FT-IR
instrument (FlowIR from Mettler Toledo) was used and thesignal at 1128 cm−1 was monitored (Figure 2a) until the steadystate was reached (Figure 2b).

The generation of the carbanion from triﬂuoromethane bydeprotonation has been extensively investigated and numerous
reports on the lifetime of this intermediate suggest that it isprone to rapid ﬂuoride atom loss and conversion into theextremely reactive diﬂuorocarbene intermediate.57−62 Despite
the increasing interest in the cost-eﬃcient and sustainable useof CF3H as triﬂuoromethylating reagent, there are still concerns
relating to its clean applications and interception in organic
synthesis programs.
Here we describe a continuous chemical approach for the useof CF3H as a source of triﬂuoromethanide anion, and its direct
use as a nucleophile to react with a range of carbonylcompounds and chlorosilanes. We demonstrate the practicalbeneﬁts derived from the introduction of the Fourier transform
infrared (FT-IR) and the nuclear magnetic resonance (NMR)
in-line analytic tools for the accurate dosing of CF3H gas andthe quantitative trapping of the highly reactive and unstable
triﬂuoromethanide anion intermediate.

■

RESULTS AND DISCUSSION
A ﬁrst screening of conditions highlighted that the temperature,
residence time, pressure, and mixing were all crucial reaction
parameters. The process setup was particularly pivotal to reachthe optimum reagent stoichiometry and avoid collateralreactions due to the decomposition of the triﬂuoromethanide
anion (Figure 1a). A four-way cross connection valve for highpressure was installed to allow eﬃcient mixing of the threereaction streams (ﬂow rate 0.2 mL/min each) containing
respectively the base, the electrophile, and the CF3H solution.
The resulting mixture was then passed through a PTFE coilreactor (14 mL). Both the mixing zone and the reaction zone
were maintained at a controlled temperature (−20 °C) by using

Figure 2. (a) In-line FT-IR monitoring. (b) Trend of the signal at1128 cm−1 assigned to CF3H.

Aiming to quantify the concentration of CF3H in the eﬄux
stream from the coil reactor (−20 °C), a solution of α,α,αtriﬂuorotoluene (PhCF3) in THF (0.3 M) was used as internal
standard and, thus, pumped through the stream C (ﬂow rate
0.2 mL/min). The signal at 1328 cm−1 in the corresponding
FT-IR spectrum was monitored until the steady state wasreached (Figure 3a). At this point a 19F NMR spectrum wasrecorded (Figure 3b), using the in-line benchtop NMR
machine (43 MHz, Spinsolve from Magritek) installed soonafter the in-line FT-IR device. Comparing the integral values ofthe signals assigned respectively to PhCF3 (singlet at −63.46ppm) and to CF3H (doublet at −79.49 ppm), it wasdetermined the concentration of the gas dissolved in thesolution under these conditions, equated to 0.738 M.
Once the exact amount of CF3H in the reaction mixture was
known, we could then optimize the concentrations of the otherreagents involved in the CF3H deprotonation/electrophiletrapping sequence. The activation of ﬂuoroform with potassiumbis(trimethylsilyl)amide (KHMDS) and addition of the formed
triﬂuoromethanide anion to carbonyl compounds in batchmode was described by Prakash et al. The resulting ﬂuorinatedproducts were obtained with modest to good yields (10−81%
yields), depending on the substrates.60 The addition of CF3H
was realized by bubbling the gas into the reaction mixture overdiﬀerent times and with diﬀerent ﬂow rates. Aiming todemonstrate the importance of the accurate dosing of CF3H
on the productivity of the reaction, a screening of the optimum
reagent concentrations was conducted, using KHMDS as a base

Figure 1. (a) Schematic of the ﬂow reactor setup using three pumps(FRA = FRB = FRC = 0.2 mL/min), a tube-in-tube reactor (1.0 m of
AF-2400 tubing), a PTFE coil reactor (14 mL), a cooling device (−20°C), a FT-IR instrument, and a benchtop NMR machine (43 MHz), aback pressure regulator (75 psi). (b) Picture of the apparatus.
B

DOI: 10.1021/acssuschemeng.7b04012
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ACS Sustainable Chemistry & Engineeringof 3a was observed, together with only traces (0.1%) of 4a(Table 1, entry 5). By contrast, the trimethylsilyl ether 4a wasformed exclusively when a strong trimethylsilyl donor, such as
chlorotrimethylsilane (TMSCl), was used as additive (Table 1,entry 6). Literature data from magnetic resonance experimentsof KHMDS suggest it exists in THF solution as a polymeric
THF-solvate [(KHMDS)2(THF)2]∞ where molecules ofsolvent can be displaced by Lewis donors, causing themonomerization of the complex.63 It is likely that when an
excess of KHMDS is present in the reaction mixture, apolymeric THF-solvate [(KHMDS)2(THF)2]∞ exists and,
spontaneously, leads to the transfer of the trimethylsilyl moiety
to oxygen, due to a proximity eﬀect. The presence of HMDS
could then cause the decomplexation of the polymeric THFsolvate.
The real-time 19F NMR monitoring provided important
information concerning the reaction progress under theconditions described in Table 1, entry 3, where a mix of 3aand 4a (ratio 58:42) was observed in the crude reaction
mixture. According to the NMR spectra recorded in-line,
compound 4a should be generated ﬁrst (Figure 4b). The
formation of the alcohol 3a is delayed with respect to 4a andcould be ascribed to the progressive decomplexation of thepolymeric THF-solvate [(KHMDS)2(THF)2]∞ induced by theformation of HMDS during the CF3H deprotonation. This
would give rise to the gradual formation of 3a (see Table 1,entry 5). Also the hypothesis of a progressive cleavage of thetrimethylsilyl group from 4a was taken into account, whereby
the ﬂuoride anion, derived hypothetically from the decomposition of the triﬂuoromethanide anion, would be responsible.
According to this explanation, ﬂuorotrimethylsilane (TMSF)
would be formed simultaneously (Figure 4a). However, nosignal in the 19F NMR spectra could be assigned to thiscompound (Figure 4b).
The protocol which has been developed for the generation of
triﬂuoromethyl carbanion and its in situ trapping withbenzophenone (Table 1, entry 2) was beneﬁcial with respect
to the corresponding batch method,60 in terms of reaction time
(23 min vs 12 h), accurate control of CF3H dosing, productivity(4.6 vs 0.225 mmol/h), and more importantly, complete
consumption of the CF3H used in the process.

Figure 3. (a) In-line FT-IR monitoring of the signals respectively at
1128 cm−1 (CF3H) and at 1328 cm−1 (PhCF3). (b) In-line 19F NMR
spectrum of the solution containing PhCF3 as internal standard(−63.46 ppm) and CF3H (−79.49 ppm).

with benzophenone 2a as an electrophile (Table 1). When an
excess of CF3H (2.46 equiv) was reacted with benzophenone(1.0 equiv) and KHMDS (1.16 equiv), the alcohol 3a was
obtained smoothly (93% conversion) in 30 min (Table 1, entry1). When the concentration of the electrophile and the basewere both increased (1.0 M), keeping constant the concentration of CF3H (0.738 M), full conversion to the alcohol 3a
was observed (Table 1, entry 2; conversion 99%). Interestingly,
the formation of O-protected alcohol 4a was detected when an
excess of base was used with respect to benzophenone and
CF3H. Increasing the concentration of KHMDS led toincreased formation of 4a (Table 1, entries 3−4). Bis(trimethylsilyl)amine (HMDS), which is formed during the
deprotonation step of CF3H by KHMDS, is reported to be aweak trimethylsilyl donor. In an eﬀort to study its role in theformation of the trimethylsilyl ether 4a, HMDS (0.8 M) was
added to the reaction mixture. In this case a selective formation

Table 1. Screening of the Optimum Reagent Concentrations during the Triﬂuoromethyl Carbanion Generation and In Situ
Trapping with Benzophenone 2aa

a

entry

[2a], M

[KHMDS], M[CF3,H], M[additive], M

ratio 3a:4aconversion, %

1
2
3
4
5
6

0.3
1.0
0.3
0.15
0.3
0.3

0.35
1.0
1.0
1.0
1.0
1.0

0.738
0.738
0.738
0.738
0.738
0.738

none
none
none
none
HMDS, 0.8
TMSCI, 0.3

100:0
100:0
58:42
29:71
99.9:0.1
0:100

93
99
99
99
71
37

Conversions were determined by NMR, using PhCF3 as internal standard.
C

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ACS Sustainable Chemistry & Engineering

Next, the preparation of triﬂuoromethyl carbinols 6a−6g
starting from a number of aldehydes was explored. Shibata et al.
reported on the use of sterically hindered organo-superbases tostabilize the naked triﬂuoromethanide carbanion and enable thetrapping with aldehydes.59 Aiming to develop a moresustainable process for large-scale production, we investigated
the use of a less expensive non-nucleophilic strong base(weaker than amide bases), such as potassium tert-butoxide (tBuOK). While this reaction is reported to perform well in
dimethylformamide (DMF), which acts as triﬂuoromethylanion
reservoir,64 the conversion to the corresponding ﬂuorinatedproducts occurs in modest yields when the same reaction is
performed in pure THF.60
Similar moderate results were obtained when a mixture of
CF3H, t-BuOK, and benzaldehyde 5a was reacted in ﬂow, using
the same ﬂow setup developed for the nucleophilic
triﬂuoromethylation of the ketones 2. A screening of thereaction conditions and the process design demonstrated that a
noticeably improved result could be obtained when a solutionof aldehyde 5 in DMF (0.3 M) was mixed at −20 °C with two
streams containing respectively CF3H (0.738 M in THF) and tBuOK (1.0 M in THF). The resulting mixture, reacting at −20°C within a PTFE reactor coil (16 mL, residence time 27 min),gave the corresponding ﬂuorinated carbinols 6a−6g withexcellent results (Chart 2; yields after chromatographic

Figure 4. (a) Possible reaction pathways of triﬂuoromethane (CF3H)
with benzophenone (PhCOPh) in the presence of KHMDS. (b) Inline 19F NMR monitoring of the reaction mixture over the time
containing 4a (at −73.06 ppm), 3a (−73.30 ppm), and CF3H (−79.49
ppm).

Chart 2. Synthesis of Fluorinated Carbinols 6a−6g via
Generation of Triﬂuoromethanide Carbanion and In Situ
Trapping with Aldehydes 5a−5g with In-Line FT-IR and
NMR Monitoring

The insertion of a fourth stream containing a solution of
TMSCl in THF (0.3 M; pump D: ﬂow rate 0.6 mL/min; Chart
1) and the introduction of an additional PTFE coil reactor (16mL) permitted the in-line derivatization of the alcohols 3, andtherefore gave access to a number of substituted trimethylsilyl
ethers 4a−4f with excellent yields (isolated yields after
chromatographic puriﬁcation 71−95%) and in a relatively
short time (1.15 h).
Chart 1. Synthesis of O-Trimethylsilyl Fluorinated Ethers
4a−4f by an Intensiﬁed Process (Triﬂuoromethyanide
Carbanion − Nucleophilic Addition to Ketones 2a−2f −Product Derivatization) with In-Line FT-IR and NMR
Monitoring

puriﬁcation 75−97%). Importantly, the real-time 19F NMR
monitoring conﬁrmed that no ﬂuorinated byproduct wasformed under these reaction conditions and that complete
consumption of CF3H was achieved.
Finally, we extended our study to the development of acontinuous scalable production of ﬂuorinated organosiliconcompounds, which are extensively applied in organic synthesis
as ﬂuoroalkylation reagents.65 There is a growing interest in
developing more environmentally benign methods for theirlarge-scale production, which would circumvent the use of theozone-depleting bromotriﬂuoromethane (CF3Br) as startingD

DOI: 10.1021/acssuschemeng.7b04012
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ACS Sustainable Chemistry & Engineering

Figure 5. (a) Schematic of the ﬂow reactor setup for the synthesis of triﬂuoromethyltriethylsilane 8 using three pumps (FRA = FRB = FRC = 0.1 mL/min), a tube-in-tube reactor (1.0 m of AF-2400 tubing), a PTFE coil reactor (14 mL), a cooling device (−40 °C), a FT-IR instrument, and abenchtop NMR machine (43 MHz). (b) In-line 19F NMR spectrum of the solution containing PhCF3 as internal standard (−63.46 ppm) and CF3H(−79.49 ppm) at −40 °C. (c) In-line FT-IR analysis by monitoring the trend of CF3H and Et3Si CF3. (c) In-line 19F NMR analysis by monitoring
the trends of CF3H and Et3Si CF3.

■

material.66 In particular, we turned our eﬀorts to the
preparation of triﬂuoromethyltriethylsilane 8, which is widelyused as a triﬂuoromethyl precursor.67,68 The reaction
conditions were accurately investigated, taking advantage ofthe real-time monitoring of the reaction mixture. It was foundthat a lower temperature (−40 °C) and longer residence time
(57 min) were crucial parameters to succeed in the formationof 8. The concentration of CF3H in the solution under the new
ﬂow setup (Figure 5a; T = −40 °C; FRA = FRB = FRC = 0.1
mL/min) was measured by using the in-line 19F NMR analysis(Figure 5b; α,α,α-triﬂuorotoluene as internal standard, 0.3 M;[CF3H] = 0.732).
The reaction was continuously monitored by FT-IR (Figure5c) and by 19F NMR (Figure 5d), discovering that an excess ofchlorotriethylsilane (Et3SiCl, 2M), used as electrophile, wascrucial to suppress the formation of triethylsilyl ﬂuoride(Et3SiF; signal at −151.02 ppm in the 19F NMR spectrum)as byproduct. Under these reaction conditions, full consumption of CF3H was observed (Figure 5c, blue line, trendof the peak at 1132 cm−1; Figure 5d, disappearance of the
doublet at −79.49 ppm) and clean formation of compound 8
was detected (Figure 5d, green line, trend of the peak at 1251
cm−1; Figure 5d, appearance of the singlet at −61.44 ppm).

CONCLUSION

In conclusion, a synthetic approach which allows the safe
utilization of a potent greenhouse gas, such as triﬂuoromethane,
has been developed. With exploitation of the discovered
permeability of the Teﬂon AF-2400 membrane to CF3H, acontrolled introduction of this gas into the reaction mixture wasachieved. The real-time spectroscopic analysis (FT-IR and
NMR) enhanced the precise measurement of CF3H in thesolution, with clearly beneﬁts the selectivity in the products
formation. The process described was fully contained and any
possible dispersion of ﬂuoroform into the atmosphere was
accurately controlled and minimized. The fast and complete
interception of the triﬂuoromethyl carbanion intermediate by
ketones, aldehydes, and chlorosilanes gave access to functional
ﬂuorinated products with high yields. The spontaneous
decomposition of the triﬂuoromethyl carbanion intermediate
to diﬂuorocarbene was completely suppressed, resulting in
simpler downstream processing. The successful production of
triﬂuoromethyltriethylsilane, as triﬂuoromethylation reagent,also could extend applications of the ﬂow reactor setup to thetriﬂuoromethylation of enolizable carbonyl compounds, whichwere not suitable substrates in this work. The reactor design
E

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■

ASSOCIATED CONTENT

S Supporting Information*

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acssuschemeng.7b04012.
Synthetic procedures and characterization of compounds
(PDF)

■

AUTHOR INFORMATION

Corresponding Authors*E-mail: bm450@cam.ac.uk.
*E-mail: svl1000@cam.ac.uk.
ORCID

Steven V. Ley: 0000-0002-7816-0042
Present Addresś́
Departamento de Quimica
Orgánica y Quimica
Inorgánica,
Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain.
†

Author Contributions

The paper was written through contributions of all authors. All
authors have given approval to the ﬁnal version of the paper.
Notes

The authors declare no competing ﬁnancial interest.

■

ACKNOWLEDGMENTS
The authors acknowledge Dr. Mikhail A. Kabeshov and Dr.
Philip R. D. Murray for helpful discussions and suggestions.
The authors are also thankful to the EPSRC (Award Nos. EP/
K009494/1, EP/K039520/1 and EP/M004120/1) for ﬁnancial
support.

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