Highly flexible fibre-optic ATR-IR probe for inline reaction monitoring

Article abstract of DOI:10.1021/op0601767

Near infrared (IR) applications have considerably profited from the use of flexible and robust fibre-optical probes. So far, a comparable technique for mid-IR was not available due to low stability and lack of robustness of the fibres. We report the use of a newly developed miniaturised diamond ATR-probe with high chemical resistance and pressure resistance based on robust fibre optics. The routine and convenient application in a glove box to highly air- and oxygen-sensitive reactions on a millilitre scale is reported, as well as the monitoring of a solventless reaction on a litre scale.

Full text of DOI:10.1021/op0601767

Organic Process Research & Development 2007, 11, 94−97
Highly Flexible Fibre-Optic ATR-IR Probe for Inline Reaction Monitoring
Clemens B. Minnich,† Pascal Buskens,† H. Christian Steffens,†,‡ Patrick S. Ba¨uerlein,†,§ Leonid N. Butvina,|
Lukas Ku¨pper, Walter Leitner,† Marcel A. Liauw,† and Lasse Greiner*,†
Institut fu¨r Technische und Makromolekulare Chemie, RWTH Aachen UniVersity, Worringerweg 1, D-52074 Aachen,
Germany, Fiber Optic Research Center, General Physics Institute, VaViloV Str. 28, RUS-111991 Moscow, Russia, and
infrared fiber sensors, Im Gillesbachtal 33, D-52066 Aachen, Germany
Abstract:
the application of a highly flexible fibre optical ATR-IR
probe for inline monitoring of reactions of current interest.
Near infrared (IR) applications have considerably profited from
the use of flexible and robust fibre-optical probes. So far, a
comparable technique for mid-IR was not available due to low
stability and lack of robustness of the fibres. We report the
use of a newly developed miniaturised diamond ATR-probe
with high chemical resistance and pressure resistance based on
robust fibre optics. The routine and convenient application in
a glove box to highly air- and oxygen-sensitive reactions on a
millilitre scale is reported, as well as the monitoring of a
solventless reaction on a litre scale.
Results and Discussion
A newly developed probe for IR measurements with the
ATR technique based on previous designs16 has been used
for monitoring purposes (Figure 1).
As the internal reflection element (IRE), a diamond prism
is welded to the gold plated Hastelloy body of the probe,
giving rise to two internal bounces. The source light beam
is conducted to the IRE and back by silver halide fibres. The
connection of the fibres with the spectrometers is achieved
by standard SMA plugs. Probes have been attached to
VECTOR 22 and IRCube FTIR spectrometers (BrukerOptics,
Ettlingen, Germany) and to Avatar 380 and Nexus 5700
FTIR spectrometers with a slightly modified MidIR Fiber-
Port accessory (Thermo Inc., Waltham, MA, U.S.A.), demon-
strating a broad compatibility with commercial equipment.
Due to the unique chemical properties of the diamond
prism and of the gold layer covering the metal parts, the
probe is resistant towards a broad variety of reaction media
such as organic solvents, aqueous media, ionic liquids (ILs),
and supercritical fluids. Moreover, pressures up to 300 MPa
and temperatures up to 460 K have been applied without
significant influence on the system performance. Sterilisation
of the probe head with steam as required for pharmaceutical
or biotechnological purposes is straightforward. The geom-
etry allows the use of commercial fittings (Gyrlock- or
Upchurch-type) for 1/4 in. tubing in order to achieve leak
proof and gastight sealings.
Introduction
Inline reaction monitoring has turned out to be highly valu-
able for the efficient control of chemical processes and is a
key tool in process analytical technology (PAT).1-5 For ob-
taining real-time information on chemical composition, mid-
IR spectroscopy has proven to be highly versatile, especially
when performed with the attenuated total reflectance (ATR)
technique.6-15 Without the need for optical transmission
paths, integration into existing experimental setups is easily
achieved and not restricted by optical density. Here we report
* Corresponding author. E-mail: greiner@itmc.rwth-aachen.de. Fax:
+49-241-80 626484.
† Institut fu¨r Technische und Makromolekulare Chemie, RWTH Aachen
University.
‡ Current address: BayerMaterialScience AG, Dormagen/Germany.
§ Current address: Eindhoven University of Technology, Eindhoven/The
Netherlands.
| Fiber Optic Research Center, General Physics Institute.
infrared fiber sensors.
With an overall transmission path of 0.6 to 4 m inside
the light conductors and 2.6 mm inside the IRE, the residual
spectral intensity in the wavenumber range between 4000
and 600 cm-1 is by far sufficient for standard protocol
measurements (Figure 2). Sensitivity is decreased between
2300 and 1900 cm-1 due to the absorption of the diamond.
In order to illustrate the variety of possible applications,
three types of reactions of current interest have been
investigated: the solvent-free synthesis of ILs, the organo-
catalysed aza-Baylis-Hillman reaction, and the transition
metal-catalysed hydroamination.
(1) Bakeev, K. A. Process Analytical Technology - Spectroscopic tools and
implementation strategies for the Chemical and Pharmaceutical Industries;
Blackwell Publishing Ltd.: Oxford/UK, 2005.
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Spectrochim. Acta A 2004, 60(14), 3259.
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Spectrosc. 2004, 58(7), 804.
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Giudici, R.; Araujo, P. H. H. Ind. Eng. Chem. Res. 2004, 43(23), 7282.
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New York, 1967.
(9) Zogg, A. Ph.D. Thesis, ETH Zu¨rich, Zu¨rich/Switzerland, 2005.
(10) Zogg, A.; Fischer, U.; Hungerbu¨hler, K. Chem. Eng. Sci. 2004, 59, 5795.
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Chem. B 2005, 109, 16794.
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(15) Liauw, M. A.; Oderkerk, B.; Treu, D. Chem. Eng. 2006, 7, 56.
Solvent-Free Synthesis of Ionic Liquids. 1-Ethyl-3-
methylimidazolium ethyl sulfate ([EMIM]EtSO4) is an IL
with a melting point below 208 K and an important
(16) Heise, H. M.; Ku¨pper, L.; Butvina, L. N. Anal. Bioanal. Chem. 2003, 375,
1116.
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10.1021/op0601767 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/23/2006

Figure 1. Fibre probe by ifs-aachen with diamond prism as
internal reflection element and a 1 Euro-coin (diameter 23 mm)
for size relation.
Figure 4. Molar fractions of reactants as a function of time
during a fed-batch synthesis of [EMIM]EtSO4. (Inset) Two-
step decrease in diethyl sulfate concentration.
Figure 2. Single-channel spectrum of the ATR probe for
different lengths of the fiber optics (0.8-2.5 m, left scale) and
the resulting referenced transmission spectrum (gray, right
scale) (32 scans, scan resolution: 4.0 cm-1, spectrometer:
Bruker Vector 22)
Figure 5. Setup with the ATR-IR probe inside an argon
purged glove box.
Figure 6. Hydroamination of 1,3-cyclohexadiene with aniline.
Figure 3. Synthesis of [EMIM]EtSO4 from MIM and DES.
regions between 1650 and 650 cm-1. Thus, the molar
fractions of the two substrates and the product can reliably
be monitored (Figure 4).
intermediate product for halide-free second-generation ILs.17
It is accessible in a solvent-free synthesis via the N-alkylation
of 1-methylimidazole (MIM) with diethyl sulfate (DES,
Figure 3).18,19 The reaction has been studied in a solvent-
free fed-batch experiment.
In a typical experiment, DES was charged to a stainless
steel reactor of 1.8 L total volume, and a stoichiometric
amount of MIM was added in 12 consecutive injections.
From the time-resolved spectra, quantitative information
on the composition of the reacting mixture was gained by
multivariate calibration with PLS (partial least-squares)
algorithms implemented in the OMNIC software (Thermo
Inc., Waltham , MA, USA). For calibration, spectra of binary
and ternary mixtures of the involved compounds were
subjected to a PLS regression in selected wavenumber
The accuracy of the quantification even allows distin-
guishing between the decreases in molar fractions due to
dilution and the reaction, showing that mixing times in the
reactor are fast compared to times of reaction. Detailed
kinetic investigations have been published elsewhere.20
Palladium-Catalysed Hydroamination of Alkenes. The
kinetics of the Pd-catalysed hydroamination of 1,3-cyclo-
hexadiene with aniline as developed by Hartwig21-23 (Figure
6) have been investigated in small-scale batch experiments
(typically 4 mL vessels) in a glove box setup (Figure 5).
The probe is introduced into the glove box via a dedicated
fitting manufactured for both optical fibres with the spec-
(20) Minnich, C. B.; Ku¨pper, L.; Liauw, M. A.; Greiner, L. 2006. Manuscript
submitted.
(17) Wasserscheid, P.; Hilgers, C. EP 1182196, 2000.
(18) Wasserscheid, P.; van Hal, R.; Hilgers, C. WO 2004096776, 2004.
(19) Holbrey, J. D.; Reichert, W. M.; Swatlowski, R. P.; Broker, G. A.; Pitner,
W. R.; Seddon, K. R.; Rogers, R. D. Green Chem. 2002, 4(5), 407.
(21) Kawasutra, M.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 9546.
(22) Nettekoven, U.; Hartwig, J. J. Am. Chem. Soc. 2002, 124, 1166.
(23) Lo¨ber, O.; Utsunomiya, M.; Hartwig, J. J. Am. Chem. Soc. 2003, 123, 4366.
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Figure 7. Normalised residual concentration of aniline as a
function of time at different reaction temperatures. Lines:
normalised absorption at ν˜ ) 1618 cm-1. Points: normalised
residual concentrations from external analysis by gas chroma-
tography (308 K: (b) solid line; 314 K: ([) dashed line; 323 K:
(1) dotted line.
Figure 9. Conversion vs time for the aza-Baylis-Hillman
reaction at 306 K, derived from the normalised intensity of the
product signal at ν˜ ) 781 cm-1
.
copy in the glove box setup described above. As a measure
for product concentration, the absorption at a wavenumber
of ν˜ ) 781 cm-1 was chosen (Figure 9).
Data from these measurements successfully cross validate
the data obtained from NMR spectroscopy. This displays the
potential of the presented ATR-IR setup for the monitoring
of organocatalytic reactions.
Figure 8. Aza-Baylis-Hillman reaction of N-(4-bromoben-
zylidene)-4-methyl-benzenesulfonamide with methylvinyl ke-
tone.
Conclusion and Outlook
The fibre-optic probe for ATR-IR spectroscopy presented
here has proven its value for reaction monitoring and process
control in a variety of applications. Results from kinetic
studies in noncatalytic liquid-liquid synthesis, organocata-
lytic and transition metal-catalysed transformations have been
externally validated with classical offline analytics (e.g., gas
chromatography, NMR spectroscopy) and showed an excel-
lent agreement. Reaction volumes range from 1 mL to litres,
and time scales are covered from minutes to hours. Fibre
optics allow usage in a glove box for rapid and convenient
kinetic evaluation without sampling.
trometer being placed outside the box. This nicely illustrates
the flexibility of the system, e.g. in its use for air and
moisture sensitive reactions.
The intensity of the absorption at a wavenumber of ν˜ )
1618 cm-1 was taken as a measure for the concentration of
starting material (aniline). The decrease of intensity over time
was in good agreement with gas chromatographic reference
analyses (Figure 7). The reaction was characterised for
temperature dependence, catalyst robustness, and concentra-
tion influences.24
Application of this technique revealed a pseudo-zero-order
rate law with respect to both substrates up to conversions
near 80% and a decrease in catalyst stability at elevated
temperature.
Organocatalytic Aza-Baylis-Hillman reaction. The
aza-Baylis-Hillman reaction, a Lewis-base-catalysed C-C
coupling reaction between activated alkenes and imines
(Figure 8), is of high interest for organic synthesis due to its
densely functionalised reaction products.27-30
Experimental
Solvent-Free Synthesis of Ionic Liquids. MIM and DES
were provided by Solvent Innovation (Cologne/Germany),
distilled under reduced pressure prior to use and stored under
dry nitrogen. Typical protocol for a fed-batch experiment:
DES (448 mL, 524 g, 3.40 mol) was charged into an HP 60
stainless steel tank reactor (Bu¨chi Glas Uster, Uster/
Switzerland) at 308 K. Via a thermostated dosing unit, MIM
(281 mL, 290 g, 3.53 mol) was added in 12 consecutive
injections (23 mL each).
Transition-Metal Catalysed Hydroamination of Alk-
enes. Reactions were carried out in a glove box (Braun,
Munich, Germany) under an inert atmosphere of dry argon
(purity 5.0). Typical protocol: A solution of cyclopentadienyl
palladium allyl (17 mg, 0.080 mmol) in toluene (1.0 mL)
was prepared in a 4 mL GC vial. A suspension of 3-(diphe-
nylphosphino)benzoic acid (49 mg, 0.16 mmol) in cyclo-
1,3-hexadiene (1.28 g, 1.52 mL, 16.0 mmol) was added and
stirred for 15 min. The reaction was started by adding aniline
(0.75 g, 0.72 mL, 8.0 mmol).
Kinetic studies of this reaction by NMR spectroscopy have
recently been published independently by the groups of
Jacobsen27 and Leitner.30 In both studies first-order depen-
dence on both alkene and Lewis-base concentration was
observed and a non-integer partial order was determined for
the imine concentration. An external validation of the NMR
spectroscopic monitoring was performed with IR spectros-
(24) Steffens, C. Ph.D. Thesis, RWTH Aachen University, Aachen/Germany,
2005.
(25) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811.
(26) Perlmutter, P.; Teo, C. C. Tetrahedron Lett. 1984, 25, 5951.
(27) Raheem, I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005, 347, 1701.
(28) Shi, M.; Chen, L. -H.; Li, C. -Q. J. Am. Chem. Soc. 2005, 127, 3790.
(29) Gausepohl, R.; Buskens, P.; Kleinen, J.; Bruckmann, A.; Lehmann, C. W.;
Klankermayer, J.; Leitner, W. Angew. Chem., Int. Ed. 2006, 45, 3689.
(30) Buskens, P.; Klankermayer, J.; Leitner, W. J. Am. Chem. Soc. 2005, 127
(48), 16762.
Organocatalytic Aza-Baylis-Hillman Reaction. N-(4-
bromobenzylidene)-4-methylbenzenesulfonamide (42 mg,
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0.13 mmol) and triphenylphosphine (10 mg, 0.037 mmol)
were dissolved in THF (2.0 mL). The reaction was started
by addition of methylvinyl ketone (13 µL, 11 mg, 0.15 mmol)
at 306 K.
University) for the construction of reactor setups. The IL
work has been funded within the FP 6 by the EC as part of
the IP IMPULSE, NMP 011816. Partial funding has been
granted by the German Ministry of Education and Research
(Sonderforschungsbereich 540). P.B. gratefully acknowledges
funding by the Deutsche Forschungsgemeinschaft (Gra-
duiertenkolleg 440, SPP 1179 Organocatalysis).
Acknowledgment
Our thanks go to Johannes Uihlein, Dr. Hans-Hermann
Drews, and Dr. Arno Simon (all BrukerOptics, Ettlingen/
Germany) for providing an IRCube spectrometer, technical
support, and fruitful discussions. Special thanks also go to
Ralf Thelen (Mechanical Workshop, ITMC/RWTH Aachen
Received for review August 24, 2006.
OP0601767
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