Real time observation of microwave-enhanced reactions via fast FTIR spectroscopy

Article abstract of DOI:10.1016/j.tetlet.2009.01.035

Microwave-enhanced reactions are very fast in comparison to thermal reactions. The determination of optimal end point often fails because conventional analytical methods are too slow. Therefore, we established a fast method using FTIR spectroscopy. The re

Full text of DOI:10.1016/j.tetlet.2009.01.035

Tetrahedron Letters 50 (2009) 1321–1323
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Real time observation of microwave-enhanced reactions via fast
FTIR spectroscopy
b
a
Eberhard Heller a, , Werner Lautenschläger , Ulrike Holzgrabe
*
a Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
b Mikrowellenlaborsysteme GmbH, Auenweg 37, D-88299 Leutkirch/Allgäu, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave-enhanced reactions are very fast in comparison to thermal reactions. The determination of
optimal end point often fails because conventional analytical methods are too slow. Therefore, we estab-
lished a fast method using FTIR spectroscopy. The result of the reaction control analysis is obtained
within less than 1 min.
Received 13 November 2008
Revised 21 December 2008
Accepted 9 January 2009
Available online 15 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-enhanced synthesis
Real time observation
Fast FTIR spectroscopy
1. Introduction
spectra were measured using a Bruker Alpha apparatus and
Opus software. There are two procedures A6 (Examples 1–4)
The concept of microwave-enhanced reactions in organic syn-
thesis is well established for a huge variety of reactions (see for
some examples1) which were recently summarized in reviews2
and several books.3 It is possible to shorten the reaction time in
comparison to classical heating from days or hours to minutes.
The problem of such fast reactions is to find the optimal end point
of the conversion. Typical analytical methods controlling the pro-
gress of the reaction such as NMR, TLC or HPLC often take longer
time than the reaction in the microwave. The time range varies
from several minutes to half an hour or even more depending on
the pretreatment of the sample prior to the measurement. Within
this time, the reaction progresses and by- and decomposition prod-
ucts may develop. This decreases the yield of the major product
and increases the effort to isolate the main product.
and B7 (Example 1) to prepare and measure the progress of
the reaction.
2.1. Example 1: synthesis of 1-d-sulfobutyl-2,3,3-trimethy-
lindoleine 1
Compound 1 is a starting material for the synthesis of cya-
nine dyes. Cao et al.8 synthesized 1 in dichlorobenzene within
12 h in 69% yield (see Fig. 1). We carried out the reaction in
the microwave oven with and without dichlorobenzene. In the
first case, the reaction lasted for 2 h and the yield was 75% (pro-
cedure A). Without solvent, the reaction was completed already
(procedure B) in 45 min and the yield was quantitative
(99.8%).9 The starting materials are both liquids and they absorb
the microwave irradiation properly, since their concentration is
higher in absence of solvent and they react much faster.
A part of the FTIR spectrum can be seen in Figure 2. After 45
min, the peak at 1033 cmÀ1 remained unchanged indicating the
quantitative conversion. The reaction mixture could be worked
up.
Previously, UV/vis4 and Raman5 spectroscopies were reported
to be suitable to monitor the reaction progress. Herein, we estab-
lished a fast method to observe the progress of the reaction in real
time via fast FTIR spectroscopy after microwave-assisted evapora-
tion of samples of the reaction solution. The power of the method
is demonstrated by four completely different examples.
2. Results and discussion
The following syntheses were carried out in a Milestone
+
O
N
S
N +
(CH2)4SO3
Ethos 1600 or
a Milestone Rotaprep System. The fast FTIR
O
O
-
1
* Corresponding author. Tel.: +49 931 8885467; fax: +49 931 8885494.
E-mail address: eheller@pharmazie.uni-wuerzburg.de (E. Heller).
Figure 1. Synthesis of compound 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.035

1322
E. Heller et al. / Tetrahedron Letters 50 (2009) 1321–1323
Figure 2. IR absorption bands of reaction 1.
2.2. Example 2: synthesis of 2-(3-dimethylamino-propyl)-
isoindoline-1,3-dione 2
Figure 5. Extension of the IR absorption bands of the reaction mixture after 15 and
20 min.
The formation of the imide 2 was published as both a thermal
and a microwave-enhanced method (see Fig. 3).1a The reaction
time was shortened (from hours to minutes) and the yield was im-
proved with microwaves from 85% to 91%. However, the reaction
was supposed to last for further 30 min applying the second meth-
od. On monitoring the reaction by means of procedure A, it was re-
vealed that the reaction was completed within 15 min. The
carbonyl signal of the imide at 1714 cmÀ1 was fully developed after
15 min (see Figs. 4 and 5) and increased only very slightly till 20
min. Additionally, the yield was augmented to 99%.
O
CH3CN
CH3
Br
N
N
+
Br
MW
CH3
O
2
-
2 Br
O
O
CH3
N+
H3C
N+
CH3
N
N
CH3
O
O
3
2.3. Example 3: synthesis of hexamethylenebis[dimethyl(3-
phthalimidopropyl)-ammonium] dibromide (W84) 3
Figure 6. Synthesis of W84.
W84 was synthesized in the classical way (time 2 h, yield is not
reported,10 (see Fig. 6) but was found to be 80%) and in a micro-
wave oven (time 30 min, yield 91%).1a IR monitoring at 694 cmÀ1
(see Fig. 7) revealed the reaction being finished after 21 min in
99% yield.
O
CH3
O
H2N
N
CH3
N
CH3
N
O
H3C
Toluol, p-TosOH , (SiC)n
O
O
Figure 3. Synthesis of compound 2.
Figure 7. IR absorption bands after 1, 6, 21 and 31 min.
O
CH3
H3C
CH3
H2N
OH
p-TosOH
H C
3H3C
N
OH
H
4
Figure 8. Synthesis of compound 4.
2.4. Example 4: synthesis of 2,2,4-trimethyl-1,2-dihydro-
quinolin-7-ol 4
Yi et al.11 synthesized the dihydroquinoline 4 with propyne and
Ru3(CO)12/HBF4 Â OEt2 (see Fig. 8). They achieved only 38% yield
Figure 4. IR absorption bands of phthalic acid anhydride (green) and reaction
mixture (magenta) after 15 min.

E. Heller et al. / Tetrahedron Letters 50 (2009) 1321–1323
1323
3. Conclusion
The examples clearly demonstrate that monitoring of the fast
microwave-supported reactions is possible via the FTIR method
because the preparation of the samples to be measured IR-spectro-
scopically takes normally less than 1 min. However, pretreatment
of the reaction samples for NMR or HPLC measurements can take
up to half an hour in addition to the measurement itself. TLC does
not need a sample preparation but the development time is mostly
at least 10 min. Thus, the fast FTIR method presented here is opti-
mal for the identification of the end point of the fast microwave-
enhanced reaction. Over-reactions occurring during the course of
NMR-, HPLC- or TLC monitoring can be avoided. Taken together,
monitoring a reaction by fast FTIR spectroscopy is a useful tool to
save human and material resources which can be used for other
scientific challenges.
Figure 9. IR absorption bands of the reaction mixture after 14 and 25 min.
Acknowledgement
Thanks to the German Federal Ministry of Economics and Tech-
nology for the Exist grants.
References and notes
1. (a) Schmitz, J.; Heller, E.; Holzgrabe, U. Monatsh. Chem. 2007, 138, 171; (b) Jiao,
G.-S.; Castro, J. C.; Thoersen, L. H.; Burgess, K. Org. Lett. 2003, 5, 3675; (c) Heller,
E.; Lautenschläger, W.; Holzgrabe, U. Tetrahedron Lett. 2005, 46, 1247; (d)
Giarrusso, M. A.; Higham, L. T.; Kreher, U. P.; Mohan, R. S.; Rosamilia, A. E.;
Scott, J. L.; Strauss, C. R. Green Chem. 2008, 10, 842.
2. (a) Larked, M.; Hallberg, A. Drug Discovery Today 2001, 8, 406; (b) Kappe, C. O.
Angew.Chem.,Int.Ed.2004,43,6250;(c)Kappe,C.O.Chem.Soc.Rev.2008,37,1127.
3. (a) Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH: Weinheim, 2002; (b)
Tierney, J.-P.; Lidström, P. Microwave Assisted Organic Synthesis; Blackwell:
Oxford, 2005; (c) Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005.
Figure 10. Extension of the IR absorption bands of the reaction mixture after 30, 52
and 70 min.
4. Getvoldsen, G. S.; Elander, N.; Stone-Elander, S. A. Chem. Eur. J. 2002, 8, 2255.
5. (a) Pivonka, D. E.; Empfield, J. R. Appl. Spectrosc. 2004, 58, 41; (b) Barnard, T. M.;
Leadbeater, N. E. Chem. Commun. 2005, 3615; (c) Leadbeater, N. E.; Smith, R. J.
Org. Lett. 2006, 8, 4488; (d) Leadbeater, N. E.; Smith, R. J.; Barnard, T. M. Org.
Biomol. Chem. 2007, 5, 822; (e) Leadbeater, N. E.; Smith, R. J. Org. Biomol. Chem.
2007, 5, 2770.
within 24 h. We carried out the reaction with a large excess of ace-
tone. Ninety percent of 4 could be isolated after 18 h at 25 °C.
When the reaction mixture was heated up classically to 50 °C, ace-
tone polymers were formed which were very difficult to be sepa-
rated from the desired product. In the microwave, the reaction
was completed after 25 min at 55 °C (see Fig. 9). Only small
amounts of by-product (acetone polymer) were formed after 30
min. The extension of the reaction time leads to higher amounts
of the by-product (cf., Fig. 10 showing IR absorption bands after
30, 52 and 70 min) as can be seen from the growing signal at
1701 cmÀ1 (see Figs. 9 and 10). The arrows indicate the formation
of the reaction product 4.
Monitoring of microwave-enhanced reactions by fast FTIR spec-
troscopy allows the observation of conversion progress for nearly
any chemical reaction. There is always a change in the IR spectra
of the starting materials and the product especially in the finger
print area. This is a big advantage in comparison to in situ monitor-
ing by UV/vis spectroscopy where only concentrations in the range
of 10À4 to 10À5 M can be observed. The FTIR method is superior to
the Raman assay because many common solvents are Raman
active.
6. Procedure A: The starting materials were dissolved in the reaction solvent and
a few drops of the solution were placed on a WeflonÒ plate. The plate was
treated with microwaves until the solvent was completely evaporated. A FTIR
spectrum was monitored with the plate. The microwave oven was switched on
until the reaction temperature was reached. For monitoring purposes reaction
samples were prepared in the same way, after 1 min, after 2, 3 or more minutes
until no change in the last two spectra were observed or until by- or
decomposition products appeared. The reaction mixture was immediately
cooled down to 25 °C in an air stream within 15 min and worked up.
7. Procedure B: The starting materials were mixed well without any solvent and a
FTIR spectrum of one of the starting materials was monitored. The microwave
oven was switched on until the reaction temperature was reached. The reaction
mixture was monitored as described above without evaporating the solvent.
The reaction was stopped, cooled down to 25 °C in an air stream within 15 min
and worked up.
8. Cao, H.; Xiong, Y.; Wang, T.; Chen, B.; Squier, T. C.; Mayer, M. U. J. Am. Chem. Soc.
2007, 129, 8672.
9. Synthesis of 1-d-sulfobutyl-2,3,3-trimethylindoleine 1:Twenty millimols (3.18
g) of 2,3,3-trimethyl-indole and 64 mmol (6.5 ml) of 1,4-butane sultone were
mixed well and heated up to 120 °C within 3 min. The reaction was controlled
by procedure B. After 45 min the reaction was completed and cooled down to
25 °C in an air stream within 15 min. The purple residue was stirred with 150
ml of acetone for 12 h. Within this time a pink solid precipitated. The solid was
filtered off, washed with acetone and dried i. vac. Yield: 5.90
Spectroscopic data were in agreement with Ref. 8.
g (99.8%).
The drawback of the FTIR method is applied to highly boiling
and microwave transparent solvents (e.g., xylene, decaline). They
cannot be evaporated in reasonable time.
10. Wassermann, O. Habilitationschrift, University of Kiel, Kiel.
11. Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc. 2005, 127, 17000.