Continuous preparation of arylmagnesium reagents in flow with inline IR monitoring

Article abstract of DOI:10.1021/op200275d

A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides. Furthermore, inline IR monitoring was used for the analysis of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details. The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the Grignard exchange reaction due to fast mixing and efficient heat transfer.

Full text of DOI:10.1021/op200275d

ARTICLE
pubs.acs.org/OPRD
Continuous Preparation of Arylmagnesium Reagents in Flow with
Inline IR Monitoring
Tobias Brodmann,† Peter Koos,† Albrecht Metzger,† Paul Knochel,*,‡ and Steven V. Ley*,†
†Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
‡Department of Chemistry, Ludwig Maximilians-Universit€at M€unchen, Butenandtstrasse 5-13, Haus F, 81377 M€unchen, Germany
S Supporting Information
b
ABSTRACT: A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for
Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the
preparation of functionalized arylmagnesium compounds from aryl iodides or bromides. Furthermore, inline IR monitoring was
used for the analysis of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details.
The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the
Grignard exchange reaction due to fast mixing and efficient heat transfer.
1. INTRODUCTION
2. RESULTS AND DISCUSSION
The Grignard reaction1 was discovered in 1900 and some 12
years later was deemed worthy of the Nobel Prize in chemistry.
This reaction continues to be a key component of the synthesis
chemist’s armory owing to its ability to form carbonÀcarbon
bonds in a wide variety of situations2 and additionally to afford
other useful functionality. This important transformation and the
accompanying need for the preparation of the initial organo-
magnesium reagents, has resulted in innovations and improve-
ments to the methodology3 and in our understanding of the re-
action processes.4
While many of these highly reactive Grignard reagents are
now commercially available, the ingenuity of modern organic
synthesis programs dictates the need for more functionalized
and diverse systems. Indeed, many reliable and robust proce-
dures for their batch-mode preparation are now available.5
However, given that flow chemistry, reaction telescoping and
continuous processing methods6 are beginning to impact on
the way we assemble molecules, it is therefore necessary to
develop suitable protocols for the preparation and safe delivery
of Grignard reagents under flow conditions.7 In order to
achieve this goal there are significant technical hurdles which
must be overcome. First, the pumps and related hardware such
as tubing, mixer chips and back-pressure regulators must ac-
commodate potentially exothermic processes, provide a water
and oxygen free environment and be capable of safe continuous
production of material. Ideally, there needs to be a method
for accurate inline reaction monitoring and control of the
reaction8 combined with the ability to progress the synthes-
ized organomagnesium reagent in further chemical trans-
formations.9
2.1. Inline FTIR Monitoring of Arylmagnesiumhalide For-
mation. Generally, only a few methods for preparation of
Grignard reagents are in common use in organic synthesis. Ex-
plicitly, the Grignard reagents are mostly prepared by insertion of
magnesium into a carbon/halide bond,10 by a magnesium/halide
exchange reaction,11 via carbometalation,12 hydrometalation,13 or
finally by selective deprotonation.14 In the first two cases, it has
been shown that the incorporation of LiCl as a promoter in the
Grignard formation has a remarkable influence on the reaction
outcome and on the reactivity of the resulting organometallic
species.15,16 Usually, the reactions proceed rapidly with character-
istic exothermic behavior. The reaction control on scale can be
very demanding. Considering the unique benefits of flow chem-
istry, these problems can be readily addressed. This is particularly
noteworthy during the formation and use of Grignard reagents
bearing sensitive functional groups, e.g., trifluoromethyl, chloro,
or carbonyl derivatives where the stability of the species can play a
significant role. Likewise, monitoring product quality during
Grignard formation using titration or GC and/or NMR techni-
ques can be somewhat convoluted. By contrast, the use of inline
flow IR monitoring can permit real-time return of information.17
While examples exist in the literature showing the useof IR probes
as monitoring devices,18 there is no general method for inline
analysis in the preparation of Grignard species under continuous
flow conditions.
In order to achieve this, the Grignard reagent formation was
monitored by a new inline IR instrument, where we focused on
the formation of m-methylphenylmagnesium chloride. This
solution was initially prepared in batch by a typical insertion
Here we report on the use of inline IR monitoring during the
preparation of arylmagnesium reagents and their subsequent
coupling with carbonyl compounds under continuous flow
conditions.
Special Issue: Continuous Processing 2012
Received: October 5, 2011
Published: November 01, 2011
r
2011 American Chemical Society
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reaction process using m-iodotoluene and magnesium turnings
in the presence of LiCl (Scheme 1).
and 894 cmÀ1 indicate coordination of the THF with magnesium
in the Grignard reagent (Scheme 2). The subtraction of the free
THF spectrum from that of the Grignard reagent solution shows
these peaks cleanly (Figure 2).
The concentration of the reagent and the simultaneous
conversion of substrate were verified by standard titration of
the reaction mixture with I2 and GC analysis of the protonated
product (toluene). This experiment allowed us to compare data
with the IR spectrum obtained from the same sample. We then
examined the reagent using a newly developed Mettler Toledo
ReactIR FD19 equipped with a DiComp sensor20 (Figure 1).
The measured IR spectra of THF and the 0.5 M m-methyl-
phenylmagnesium chloride solution are displayed in Figure 2.
These IR spectra clearly show resonances at 1069 and
913 cmÀ1 for free THF solvent, while the shifted peaks at 1043
The IR peaks in the fingerprint region at 764 and 711 cmÀ1
confirm the presence of the aryl moiety in the reagent.
For a more detailed analysis of this reaction mixture we ex-
amined the influence of concentration of m-methylphenylmagne-
sium chloride solution on the intensity of peaks recorded in the IR
spectrum. With this information we can then easily determine the
concentration of other Grignard solutions. A similar calibration
technique has been previously used by our group to determine
inline concentrations of intermediates in real time, and then that
information is used to accurately match the delivery of a third
stream.21 Several IR spectra with a range of THF solution con-
centrations of m-methylphenylmagnesium chloride were re-
corded to provide a suitable calibration curve. The previous
0.5 M THF solution of m-methylphenylmagnesium chloride
was diluted with dry THF to generate those 0.4, 0.3, 0.2, and
0.1 M solutions. The IR spectra (Figure 3) were measured by
directly injecting into the DiComp sensor of the ReactIR via a
5-mL syringe.
Scheme 1. LiCl-assisted formation of arylmagnesium
chloride
The recorded IR spectra are then correlated, by solvent spectra
subtraction to show only the IR spectra of the Grignard reagent.
Negative peaks at 1073 and 1058 cmÀ1 in figure 2 were caused by
mathematical effects as a consequently similar wavelength of IR
peaks of both coordinated and free THF. The calibration curve
was then created from the intensities of the IR peaks at different
concentrations. The height of the peaks at 1043 and 762 cmÀ1
was plotted against known concentrations and the calibration
curve showed almost perfect linear correlation (Figure 4).22
Scheme 2. Aryl-GrignardÀTHF complex
Figure 1. Mettler Toledo ReactIR FD.
Figure 2. IR spectrum of THF and Grignard reagent.
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Figure 3. Intensity of IR peaks of Grignard reagent at different concentrations.
Figure 4. IR calibration chart of Grignard reagent.
Scheme 3. Possible products formed in Grignard formation
reaction
combination of several fingerprint peaks can be used. In our
particular case, protonated product: 734 and 697 cmÀ1, sub-
strate: 771 and 682 cmÀ1 and homocoupling product: 775 and
697 cmÀ1 allow us to rapidly analyze the reaction mixture in
real time.
By completing a comprehensive IR study for the monitoring
process of the formation of m-methylphenylmagnesium chloride,
we could then focus on the Mg/halogen exchange reaction under
appropriate flow conditions. We therefore devised a flow reactor
arrangement to convert m-iodotoluene to the corresponding
organomagnesium reagent with real-time in situ IR monitoring
(Scheme 4).
Equipped with this chart one can easily analyze the concentra-
tion of the reactive Grignard reagent formed in the THF flow
stream. In some cases the organomagnesium reagents can be
accompanied by the formation of side products, we also used IR
spectroscopy to characterize side products as either protonated
or Wurtz coupled material (Scheme 3).
Thus, the complete IR spectra of all these components were
recorded and their fingerprint region used to track changes in
product makeup (Figure 5).
Here 1-mL PTFE sample loops were used to introduce both
aryl halide and a solution of iPrMgCl LiCl. The two reagent
3
streams were pumped23 at a rate of 0.2 mL/min and united at a
T-piece before entering a 10-mL reactor coil operating at rt. The
DiComp sensor of the ReactIR FD was placed immediately after
the coil to capture the structural information every 30 s. A final
back-pressure regulator (75 psi) was placed at the end of the flow
system to maintain constant pressure in the system. The output
stream was directed to a flask filled with a saturated aqueous
By magnification of the fingerprint region (Figure 6) the dif-
ference between the various products is instantly visible. In order
to correctly assign these products in the reaction mixture, a
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Figure 5. IR spectra of possible products in Grignard formation reaction.
Figure 6. IR spectra of possible products in Grignard formation reaction.
Scheme 4. Schematic of flow setup for Mg/halogen exchange
reaction
calculated from the IR calibration curve and the recorded peak
height. Figure 8 shows the spectrum of 0.4 M ArMgCl prepared in
batch and the IR spectrum of ArMgCl (at 45 min.) prepared using
the flow setup shown above.
The IR spectrum (blue in figure 7) clearly shows the absence
of starting material and expected formation of Grignard reagent
but without detection of any side products at least to the sen-
sitivity range24 of the measurement of the IR experiment. In the
case of the flow Mg/halogen exchange reaction, the concentration
of reagent can only be calculated using the intensity of the peak at
767 cmÀ1 due to overlap of peaks at 1038 cmÀ1 which effect the
intensity of the bands. Theoretically, the reaction would provide
the aryl Grignard reagent as 0.35 M solution in THF at steady
state. However, as we are operating under segmented flow con-
ditions, the recorded intensity of the IR peak of product
(767 cmÀ1) at 45 min indicates a 0.33 M concentration.
Additionally, we have evaluated the use of IR spectroscopy to
characterize the role of LiCl in THF. Accordingly, several IR exp-
eriments were performed. The first was a comparison of the IR
solution of NH4Cl in order to safely quench the Grignard reagent
for further analysis.
To determine the conversion and hence the concentration of
the arylGrignard reagent, theintensities ofproductIRpeaksat767
and 1043 cmÀ1 were monitored over a period of time (Figure 7).
This graph clearly shows that a level of diffusion occurs in the
flow stream as is normal for small-scale flow experiments. The
curve that isgenerated canthen be usedfor theintroduction of the
third reactant. In principle, the amount of third reactant intro-
duced can be adjusted on the basis of Grignard reagent concentration
spectra of iPrMgCl with iPrMgCl LiCl reagent in THF. The IR
3
spectra of these as 0.33 M solutions are shown in Figure 9.
As a result of LiCl incorporation one can notice shift and
intensity changes in the spectra. For example there is a small shift
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Figure 7. Real-time intensities of IR peaks of Grignard reagent.
Figure 8. IR spectra of 0.4 M ArMgCl and ArMgCl prepared using flow setup.
Figure 9. IR spectra of iPrMgCl and iPrMgCl LiCl complex.
3
difference in the corresponding key bands (1035 vs 1045 cmÀ1
,
to the Mg atom of the Grignard species. Therefore, changing to
toluene as solvent would help to define the role of THF
(Scheme 5).25
882 vs 890 cmÀ1), while the intensities are quite similar. In the
second experiment, the IR clearly indicates coordination of THF
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To this Grignard solution in toluene was added dry THF, and
the IR spectra of corresponding mixtures with 1, 2, 4, and 10 equiv
of dry THF were measured (Figure 10).
m-iodotoluene as an initial starting material for our further
optimization studies and subsequent reaction with carbonyl
compounds. A new flow reactor arrangement was therefore
developed using a combination of the Vapourtec R2+ together
with an additional external Knauer K120 pump to deliver the
carbonyl compound. As before, flow IR monitoring was used
inline to determine the concentration of organomagnesium
reagent. A 10-mL reaction coil was added to ensure complete
coupling with the carbonyl species prior to quenching with
aqueous NH4Cl (Scheme 6).
The peaks at 871, 916, 1027, and 1072 cmÀ1 were compared in
order to quantify the effect of THF coordination. The spectra demo-
nstrate the coordination of THF (peaks at 871 and 1027 cmÀ1) to
ArMgCl and that further peaks at 916 and 1072 cmÀ1 (free THF)
are observed when an excess of dry THF is added.
From these studies it is clear that inline IR spectroscopy is a
very effective procedure to ensure the quality of prepared organo-
magnesium species in solution. Additionally, the information can
be used to determine concentration of active reagents and/or the
composition of more complex reaction streams to quickly opti-
mize the reaction conditions.
2.2. LiCl-Mediated Halogen/Mg Exchange Reaction from
Aryl iodides. The preparation of functionalized Grignard reagents
via the LiCl-mediated halogen/magnesium exchange reaction is
now recognized as an important advance in the area. Following on
from the procedure reported by Krasovskiy et al., we selected
In this configuration, a solution containing iPrMgCl LiCl in
3
THF was introduced at 0.2 mL/min to join at the T-piece with a
second stream (flow rate 0.2 mL/min) containing m-iodotoluene
in THF. The combined mixture was then delivered to the first
10-mL tubular coil reactor (PTFE, 1 mm i.d.) operating at room
temperature. A second T-piece was used to combine a third
stream containing the carbonyl compound in THF at a flow rate
of 0.4 mL/min which then passes at room temperature to the
final reactor coil. The timing of the third stream addition was
adjusted on the basis of the IR readout.26 Using the previous
established IR calibration curves, we observed full conversion of
starting material after 45-min processing time.
Scheme 5. Formation of Grignard reagent in toluene using
1 equiv of THF
Following a screen of reaction parameters, we examined the
scope of the process under the optimized reaction conditions
with different aryl iodides and carbonyl compounds. The
iPrMgCl LiCl reagent was obtained from commercial sources.
3
We then examined the metal exchange process of a range of aryl
Figure 10. IR spectrum of Grignard reagent solution in toluene with added THF.
Scheme 6. Schematic of flow setup for the LiCl-mediated I/Mg exchange reaction
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Table 1. Preparation and following reactions of functionalised Grignard reagentsc
a Isolated yield after purification by flash chromatography on silica gel. b Stoichiometric LnCl3 2LiCl was premixed with the ketone and then transferred
3
to the reaction via a third pump. c Reaction conditions: 1 equiv of aryl iodide 1À7 and 1.1 equiv iPrMgCl LiCl were dissolved each in 1 mL of THF, flow
3
solvent THF 0.2 or 0.1 mL/min, reaction time 0.75 h. See Experimental Details.
iodides (1À7) to afford the corresponding Grignard reagents and
quench these inline with carbonyl components to give final cou-
pled products (Table 1).
All products 11À20 were isolated in good to excellent yields.
Seemingly, the reactions of the Grignard reagents with carbonyl
compounds under the continuous flow conditions were superior
in most cases when compared to batch reactions. The additional
formation of up to 20% of the ketone byproduct via Oppenhauer
oxidation can be observed when the reactions are conducted in
batch mode at room temperature. For this reason batch reactions
are best conducted at À10 °C. In some of our flow experiments
for the addition of Grignards to ketones (14 and 15, entries 4 and
5, Table 1), the use of a Lewis acid (LnCl3 2 LiCl) avoided
3
byproduct formation through aldol reactions.27 The presence of
electron-withdrawing or -donating groups was tolerated as in
4-iodobenzotrifluoride, 3-chloroiodobenzene, and 3-iodoaniline
as substrates (entries 6, 7, and 8, Table 1). In all these cases the
corresponding Grignard reagent was formed within 45 min and
reacted to give the alcohols (16À18) after coupling with tolyl
aldehyde 8. We have also examined the formation of a Grignard
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Scheme 7. Schematic of flow setup for the LiCl-mediated Br/Mg-exchange reaction
Table 2. Preparation and the following reactions of functionalised Grignard reagentsb
a Isolated yield after purification by flash chromatography on silica gel. b Reaction conditions: 1 equiv of aryl bromide 20À25 and 1.1 equiv
iPrMgCl LiCl were each dissolved in 1 mL THF, flow solvent THF 0.1 mL/min, reaction time 2.2 h. See Experimental Details.
3
reagent containing nitrile or ester functionalities. With a nitrile
group present, the reaction proceeds well (entry 9, Table 1).
Although for aryliodides containing an ethylester group we
obtained only moderate yields (62% yield, entry 10, Table 1)
due to side reactions. In order to examine the scalability of the
Grignard formation in continuous flow process, we have prepared
functional groups.28 While optimizing the Grignard formation an
increase in homocoupling product at higher temperatures was ob-
served, in particular when starting from electron-rich aromatic
bromides. We therefore focused our attention on activated aryl
bromides (1À3), which required shorter processing time (2 h).
The flow apparatus was constructed similarly to the previous ar-
rangement (Scheme 7).
Using aryl bromides as starting materials the three flow stream
system again utilises a combination of the Vapourtec R2+ and an
external Knauer K120 pump. However, a modified 20-mL
tubular coil (PTFE, wm mi.d.) was used to accommodate the
slower Mg/bromide exchange reactions. Typically, the solution
alcohol 11 on a 100 mmol scale. The larger volumes of iPrMgCl LiCl
3
that are involved required pumping of the starting materials
directly through the pump heads of the Vapourtec R2/4+ flow
unit. Here 19.6 g of compound 11 was obtained over 9.5 h pro-
cessing time without any visible precipitation caused by hydro-
lysis reaction. The yield of the pure isolated product (93% yield)
matched closely the yield of the small-scale reaction.
containing iPrMgCl LiCl in THF was introduced at 0.1 mL/min
3
to mix with the second stream (flow rate 0.1 mL/min) containing
aryl bromides 21À25 in THF. A further T-piece was used to
combine the organomagnesium reagent with a third aldehyde
stream. Similar to earlier reactions, IR monitoring was used to
2.3. LiCl-Mediated Halogen/Mg Exchange Reaction Using
Aryl bromides. Aryl bromides are known to be less reactive in
the exchange reaction and often require higher reaction tempera-
tures, which are not compatible with the presence of sensitive
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coordinate the addition of the third stream (flow rate: 0.2 mL/
min) followed by a further 5-mL reaction coil (PTFE, 1/16" o.d.)
held at room temperature. Finally, the output from this coil was
directed into a saturated aqueous ammonium chloride solution.
The results from these experiments using aryl bromides and
p-tolualdehyde are shown in Table 2.
The initial exchange reaction of 3,4-dichlorobromobenzene
21 (entry 1, Table 2) and 2-chlorobromobenzene 23 (entry 3,
Table 2) are very efficient and comparable with aryl iodides. The
procedure can be readily adapted for bromopyridines as starting
materials that led to alcohols 29 and 30 (entries 4 and 5, Table 2)
in high yields.
integrated 9 bounce attenuated total reflectance (ATR) gold
sealed diamond sensor (referred to as DiComp) that allows
in situ, real-time monitoring of a continuous flow stream. The full
infrared spectral region is available with this micro flow cell
(650À1950 cmÀ1 and 2250À4000 cmÀ1) excluding the diamond
“blind spot” which only allows very weak absorbance in this
region. The IR flow cell has a removable head, allowing for easy
cleaning, and an internal volume of 50 μL. It can be heated up to
120 °C using an external controller, and it can be operated at up to
7 bar pressure. OmniFit connections (1/4-28-UNF) enable the
IR flow cell to be easily incorporated into any continuous flow
chemical processing setup.
An integrated resistive thermal device (RTD) temperature
sensor is also built into the cell in order to track its temperature,
paying deference to the fact that the IR spectroscopy is tempera-
ture dependent. While the flow stream is running through the cell,
scans are taken at predefined intervals. The system is controlled,
and the raw data are collected and analyzed by the iC IR reaction
analysis software (version 4.2).
The IR spectra of Grignard solutions prepared in batch were
measured using a PTFE tubing connected to a syringe adapter,
and the solutions were injected directly to the probe from a 5-mL
syringe. The probe was dried by flushing with 15 mL of dry THF
before each IR experiment.
3. CONCLUSIONS
This new flow chemical approach leading to the formation of
Grignard reagents which are not commercially available should
find numerous applications in organic synthesis programmes.
Additionally, the newly developed microscale ReactIR flow
cell from Mettler-Toledo proved to be a convenient and versatile
inline analytical tool for analysis during Grignard formation.
4. EXPERIMENTAL DETAILS
4.1. General Remarks. NMR spectra: recorded on a Bruker
DPX-400 spectrometer. Corresponding solvent signal served as
an internal standard: for 1H NMR spectra in CDCl3—the singlet
of CHCl3 at δ 7.26 (ppm), for 13C NMR spectra in CDCl3—the
triplet at δ 77.16 ppm. Values of the coupling constant, J, are
given in hertz (Hz).
High-resolution mass spectra (HRMS): recorded with a
Waters Micromass LCT Premier spectrometer or an ABI/
MDS Sciex Q-STAR Pulsar. Unless otherwise stated, the mass
reported corresponds to the most abundant isotopes (e.g., 35Cl).
Infrared Spectra. Conventional infrared spectra were recorded
neat on Perkin-Elmer Spectrum One FT-IR spectrometer using
Universal ATR sampling accessories.
4.2. Inline FT-IR Monitoring of ArMgX Formation. Prepara-
tion of 0.5 M THF Solutionof m-Methylphenylmagnesium Chloride.
To a round-bottom flask was added LiCl (265 mg, 6.25 mmol).
The flask was heated (120 °C) under vacuum (∼1 mm Hg) for
20 min and purged several times with argon followed by the addition
of Mg turnings (304 mg, 12.5 mmol) and dry THF (10 mL). To
the resulting mixture 3-iodotoluene (0.65 mL, 5 mmol) was added
dropwise at rt (Caution! As the reaction is exothermic, an ice bath was
used to cool the mixture if the temperature exceeded 50 °C!). After ad-
dition of the substrate the reaction mixture was stirred for 1 h at rt.
The conversion of the reaction was determined by GC. The resulting
solution of Grignard reagent was then decanted and transferred to a
dry round-bottom flask under argon. The concentration (0.5 M) of
active Grignard reagent was determined by titration with I2.
Procedure for the Real-Time IR Monitored Preparation of
m-Methylphenylmagnesium Chloride in Flow. The aryl iodide
(1.0 equiv., 0.7 mmol), was dissolved in a 1 mL of THF and
loaded into a 1 mL PTFE sample loop. The second 1 mL PTFE
loop was filled with a 0.8 M THF solution of iPrMgCl.LiCl. The
reagent mixtures were pumped at a flow rate of 0.2 mL/min.
The reaction streams were combined at the T-piece and then
directed into a 10 mL reaction coil at rt. A flow DiComp probe
of the ReactIR FD was placed immediately after the coil for real-
time IR measurements. IR spectra were recorded every 30 s.
A back-pressure regulator (75 psi) was placed at the end of the
setup. The reaction stream was then directed to a flask filled
with a saturated aqueous solution of NH4Cl.
Preparation of 0.5 M Toluene/THF (1 equiv) solution of m-
Methylphenylmagnesium Chloride. To an oven-dried round-
bottom flask were added Mg turnings (304 mg, 12.5 mmol),
THF (0.4 mL, 5 mmol), and dry toluene (5 mL) under an Ar
atmosphere. To the resulting mixture 3-iodotoluene (0.65 mL,
5 mmol) was added dropwise at rt. (As the reaction is exothermic,
an ice bath was used to cool the mixture, if the temperature exceeded
50 °C!). After addition of the substrate, the reaction mixture was
stirred for 2 h atrt. Subsequently, anadditional 5 mLofdrytoluene
was added. Different solutions of m-methylphenylmagnesium
chloride were prepared by adding dry THF. The IR spectra of
Tetrahydrofuran (THF). THF was dried by distillation from
sodium wire using Ph3CH as an indicator. Commercially avail-
able reagents were used as supplied. The reagent iPrMgCl LiCl
3
was supplied from Sigma-Aldrich (CAS: 807329-97-1).
Flash column chromatography: was carried out either manu-
ally [Merck 9385 Silica gel-Breckland 60 (0.040À0.063 mm)] or
on a Biotage SP4 chromatography apparatus using Snap cartridges
GC Analysis and Iodometric Titration. For reactions in batch,
the completion of the halogen/magnesium exchange was checked
by GC analysisusing tetradecaneas internal standard. The yield of
the magnesium reagent was determined by iodometric titration.
Flow reactions: were performed using a combination of
Vapourtec R2/R4+ and Knauer 100 pumps, equipped with PTFE
tubing(diameter 1 mm, reactor volume 10 mL). The mixing of the
solution was achieved through a standard T-piece. The system was
initially dried by flowing dry THF for 12 h at a flow rate of 0.1 mL/
min. Additionally, we ensured constant reaction conditions by
flowing dry THF for 2 h at a flow rate of 0.1 mL/min before in-
jection of the reaction solutions. The injection ports were flushed
with 5 mL of dry THF before filling the PEEK loops with the
starting materials.
The FT-IR device used in this work is a ReactIR FD fitted with
a room temperature deuterated triglycine sulfate (DTGS) de-
tector. The ReactIR instrument was directly connected to a
newly developed, microscale flow cell. The flow cell comprises an
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0.5 M m-methylphenylmagnesium chloride solution (in toluene)
with 1, 2, 4, and 10 equiv of THF are shown in Figure 10.
4.3. General Procedure for the LiCl-Mediated I/Mg Ex-
change Reaction Using Aryl Iodides 1À7. Procedure for Real-
Time IR-Monitored Preparation of Grignard Reagents in Flow and
Their Addition to Aldehydes/Ketones. Two flow streams were
pumped by the Vapourtec R4/R2+: stream 1 containing a solution
143.9, 138.2, 128.5, 128.45, 128.4, 127.5, 127.3, 126.6, 123.7,
76.3, 21.6; ESI-HRMS [M À H+] calculated for C14H13O:
197.0961, found: 197.0964.
Furan-2-yl(p-tolyl)methanol (13): 1H NMR (400 MHz,
CDCl3) δ 7.39 (d, J = 0.9 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H),
7.19 (d, J = 7.9 Hz, 2H), 6.32 (dd, J = 3.1 Hz, 1.8 Hz, 1H), 6.13 (d,
J = 3.2 Hz, 1H), 5.78 (s, 1H), 2.61 (br s, 1H), 2.38 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 156.3, 142.5, 138.1, 137.9, 129.2,
126.7, 110.3, 107.3, 70.1, 21.2; ESI-HRMS [M À H+] calculated
for C12H11O2: 187.0754, found: 187.0757.
of iPrMgCl LiCl (1.1 equiv solved in 1 mL THF) loaded into a
3
1 mL PEEK loop and stream 2 containing aryl iodide 1À7
(1 equiv dissolved in 1 mL of THF). The mixtures were pumped
(flow rate 0.2 mL/min) and mixed at a T-piece before entering the
reactor (10 mL) at room temperature. The combined streams
weredirectedtothe IRflow cellof theReactIR-FDvia a PTFEcoil.
The mixture was then united with a third solvent stream (flow rate
0.4 mL/min) of the aldehyde or ketone (1.1 equif in 2 mL THF)
via a second T-piece. The installation of two back pressure re-
gulators (2 Â 75psi) beforethe secondT-piece was used to ensure
unidirectional flow through the PTFE coil (10 mL). Onexiting the
PTFE coil, the product flow stream was directed directly into a
flask filled with a saturated aqueous solution of NH4Cl. The sus-
pension was transferred to a separating funnel. The organic phase
was separated and the aqueous phase washed with CH2Cl2 (2Â).
The combinedorganicphases weredriedover MgSO4 and filtered.
The solvent was removed under reduced pressure and the crude
material purified by flash column chromatography to afford the
desired alcohols 11À20.
1-Phenyl-1-(m-tolyl)ethanol (14): 1H NMR (400 MHz,
CDCl3) δ 7.48À7À44 (m, 2H), 7.38À7.32 (m, 2H), 7.31À
7.28 (m, 1H), 7.28À7.26 (m, 1H), 7.25À7.22 (m, 2H), 7.13À
7.07 (m, 1H), 2.37 (s, 3H), 2.38 (br s, 1H), 1.97 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 148.2, 148.1, 137.8, 128.3, 128.2,
127.8, 127.0, 126.6, 126.0, 123.1, 76.3, 31.0, 21.7; ESI-HRMS
[M À H+] calculated for C15H15O: 211.1117, found: 211.1114.
1-(m-Tolyl)cyclohexanol (15): 1H NMR (400 MHz, CDCl3)
δ 7.38 (s, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H),
7.11 (d, J = 7.3 Hz, 1H), 2.41 (s, 3H), 1.93À1.74 (m, 7H),
1.74À1.62 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 149.6,
137.8, 128.2, 127.5, 125.5, 121.7, 73.2, 39.0, 25.7, 22.3, 21.7; EI-
MS [M+•] calculated for C13H18O: 190.1352, found: 190.1360.
p-Tolyl(4-(trifluoromethyl)phenyl)methanol (16): 1H NMR
(400 MHz, CDCl3) δ 7.60 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz,
2H), 7.23 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.79
(s, 1H), 2.78 (br s, 1H), 2.37 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 147.9, 147.8, 140.4, 138.0, 129.5, 126.8, 126.7, 125.5,
125.4, 75.7, 21.2; ESI-HRMS [M À H+] calculated for
C15H12F3O: 265.0835, found: 265.0836.
4.4. LiClÀMediated Br/Mg Exchange Reactions Using Aryl
Bromides 21À25. Procedure forReal-TimeIR MonitoredPrepara-
tion of Grignard Reagents in Flow and Their Addition to Aldehydes/
Ketones. Two flow streams were pumped by the Vapourtec R4/
(3-Chlorophenyl)(p-tolyl)methanol (17): 1H NMR (400
MHz, CDCl3) δ 7.41 (s, 1H), 7.28À7.22 (m, 5H), 7.21À7.15
(m, 2H), 5.74 (s, 1H), 2.49 (br s, 1H), 2.37 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 146.0, 140.5, 137.8, 134.4, 129.8, 129.4,
127.6, 126.7, 124.7, 75.6, 21.2; ESI-HRMS [M À H+] calculated
for C14H12ClO: 231.0571, found: 231.0575.
R2+: stream 1 containing a solution of iPrMgCl LiCl (1.1 equiv
3
solved in 1 mL THF) loaded into a 1 mL PEEK loop and stream 2
containing aryl bromide 20À25 (1 equiv solved in 1 mL THF).
The mixtures werepumped (flow rate 0.1 mL/min) and mixed ata
T-piece before entering the reactors (2 Â 10 mL) at room temp-
erature. The combined streams were directed to the IR flow cell of
the ReactIR-FD via a PTFE coil. The mixture was then united with
a third solvent stream (flow rate 0.2 mL/min) of the aldehyde or
ketone (1.1 equiv in 2 mL THF) via a second T-piece. The in-
stallation of two back pressure regulators (2 Â 75 PSI) before the
second T-piece was used to ensure unidirectional flow through the
PTFE coil (5 mL). On exiting the PTFE coil, the product flow
stream was directed directly into a flask filled with a saturated
aqueous solution of NH4Cl. The suspension was transferred to a
separating funnel. The organic phase was separated and the
aqueous phase washed with CH2Cl2 (2Â). The combined organic
phases were dried over MgSO4 and filtered. The solvent was re-
moved under reduced pressure and the crude material purified by
flash column chromatography to afford the desired alcohols 26À30.
1
(3-Methoxyphenyl)(p-tolyl)methanol (18): H NMR (400
MHz, CDCl3) δ 7.28À7.21 (m, 3H), 7.14 (d, J = 7.9 Hz, 2H),
6.96 (d, J = 2.1 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.80 (dd, J = 8.2,
2.0 Hz, 1H), 5.77 (s, 1H), 3.78 (s, 3H), 2.33 (s, 3H), 2.27 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 201.2, 137.3, 134.7, 129.9,
128.3, 52.7, 21.1, 14.7; ESI-HRMS [M À H+] calculated for
C15H15O2: 227.1067, found: 227.1073.
1
3-(Hydroxy(p-tolyl)methyl)benzonitrile (19): H NMR
(400 MHz, CDCl3) δ 7.70 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H),
7.53 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.22 (d, J =
8.1 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.81 (s, 1H), 2.35 (s,
3H), 2.31 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 145.5,
140.1, 138.1, 131.0, 130.9, 130.0, 129.6, 129.2, 126.7, 118.9,
112.3, 75.1, 21.2; ESI-HRMS [M À H+] calculated for
C15H12NO: 222.0913, found: 222.0916.
5. ANALYTICAL DATA
1
Ethyl 4-(hydroxy(p-tolyl)methyl)benzoate (20): H NMR
m-Tolyl(p-tolyl)methanol (11): 1H NMR (400 MHz,
CDCl3) δ 7.34À7.16 (m, 7H), (7.12, br d, J = 7.3 Hz, 1H),
5.79 (s, 1H), 2.47 (br s, 1H), 2.41 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 144.1, 141.2, 138.1, 137.2, 129.2, 128.3, 127.2, 126.6,
123.7, 76.1, 21.6, 21.2; ESI-HRMS [M À H+] calculated for
C15H15O: 211.1117, found: 211.1121.
(400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.2 Hz,
2H), 7.22 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.82 (s,
1H), 4.35 (q, J = 7.1 Hz, 2H), 2.35 (br s, 1H), 2.33 (s, 3H), 1.38
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 148.9,
140.6, 137.9, 129.9, 129.7, 129.5, 126.8, 126.3, 75.9, 61.1, 21.2,
14.5; EI-MS [M+•] calculated for C17H18O3: 270.1250, found:
270.1261.
Phenyl(m-tolyl)methanol (12): 1H NMR (400 MHz,
CDCl3) δ 7.46À7.34 (m, 4H), 7.33À7.22 (m, 3H), 7.20 (br d,
J = 7.5 Hz, 1H), 7.12 (br d, J = 7.2 Hz, 1H), 5.79 (s, 1H), 2.44 (br
s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.0,
(3,4-Dichlorophenyl)(p-tolyl)methanol (26): 1H NMR (400
MHz, CDCl3) δ 7.48 (d, J = 1.7 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H),
7.23À7.13 (m, 5H), 5.69 (s, 1H), 2.57 (br s, 1H), 2.35 (s, 3H);
1111
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13C NMR (100 MHz, CDCl3) δ 144.2, 140.1, 138.1, 132.6,
131.3, 130.4, 129.6, 128.4, 126.7, 125.9, 75.0, 21.2.
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p-Tolyl(4-(trifluoromethyl)phenyl)methanol (27): 1H NMR
(400 MHz, CDCl3) δ 7.59 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz,
2H), 7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.82
(s, 1H), 2.50 (br s, 1H), 2.36 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 147.9, 147.8, 140.4, 138.0, 129.6, 126.8, 126.7, 125.5,
125.4, 75.7, 21.2; EI-MS [M+•] calculated for C14H13OCl:
232.0649, found: 232.0655.
(2-Chlorophenyl)(p-tolyl)methanol(28):1H NMR (400 MHz,
CDCl3) δ 7.65 (dd, J = 7.7, 1.4 Hz, 1H), 7.35 (dd, J = 7.9, 1.0 Hz,
1H), 7.33 (dd, J = 7.5, 1.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.23
(td, J = 7.6, 1.6 Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H), 6.17 (s, 1H), 2.55
(br s, 1H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.2,
139.5, 137.6, 132.5, 129.6, 129.3, 128.7, 128.0, 127.1, 127.0, 72.6, 21.2;
EI-MS [M+•] calculated for C15H13OF3: 266.0913, found: 266.0921.
1
Pyridin-3-yl(p-tolyl)methanol (29): H NMR (400 MHz,
CDCl3) δ 8.44 (d, J = 1.4 Hz, 1H), 8.30 (dd, J = 4.7, 1.2 Hz, 1H),
7.68 (d, J = 7.9 Hz, 1H), 7.24À7.16 (m, 3H), 7.12 (d, J = 7.9 Hz,
2H), 5.76 (s, 1H), 5.12 (br s, 1H), 2.32 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 148.0, 147.8, 140.6, 140.3, 137.6, 134.6, 129.4,
126.6, 123.6, 73.6, 21.2; ESI-HRMS [M + H+] calculated for
C13H14NO: 200.1075, found: 200.1066.
1
Pyridin-2-yl(p-tolyl)methanol (30): H NMR (400 MHz,
CDCl3) δ 8.55 (d, J = 4.8 Hz, 1H), 7.61 (td, J = 7.7, 1.7 Hz, 1H),
7.27 (d, J = 8.0 Hz, 2H), 7.21À7.12 (m, 4H), 5.73 (s, 1H), 5.04
(br s, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3,
147.9, 140.5, 137.6, 136.9, 129.4, 127.1, 122.4, 121.4, 75.0, 21.2;
ESI-HRMS [M + H+] calculated for C13H14NO: 200.1075,
found: 200.1082.
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’ ASSOCIATED CONTENT
S
Supporting Information. This material is available free
b
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Rencurosi, A. Tetrahedron 2010, 66, 3242–3247. (b) Polyzos, A.;
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of charge via the Internet at http://pubs.acs.org.
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Ortiz, R.; Guijarro, A.; Wurst, J. R.; Rieke, R. D. J. Org. Chem. 2000,
65, 5428–5430.
Corresponding Author
svl1000@cam.ac.uk
(11) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003,
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’ ACKNOWLEDGMENT
We thank Georganics Ltd. (PK), the German Academic
Exchange Service DAAD (T.B. and A.M.) and the BP Endow-
ment (S.V.L) for financial support and Mettler Toledo for useful
discussions.
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