Cold microwave chemistry: synthesis using pre-cooled reagents

Article abstract of DOI:10.1016/j.tetlet.2006.03.059

A novel experimental procedure for chemical reactions has been devised that involves mixing and then freezing the reagents (organic solvent-free) to a sub-zero temperature such as -30 °C. This frozen mixture is exposed to microwave irradiation for a brief period of time. The use of pre-cooled reagents may give a single product not obtained by traditional microwave irradiation at room temperature. Interestingly, such a product may provide information about mechanisms by identifying the first step of a multiple step reaction.

Full text of DOI:10.1016/j.tetlet.2006.03.059

Tetrahedron Letters 47 (2006) 3213–3215
Cold microwave chemistry:
synthesis using pre-cooled reagents
Ajay K. Bose,* Subhendu N. Ganguly, Maghar S. Manhas,
William He and Jeffrey Speck
George Barasch Bioorganic Research Laboratory, Department of Chemistry and Chemical Biology,
Stevens Institute of Technology, Hoboken, NJ 07030, USA
Received 8 January 2006; revised 3 March 2006; accepted 9 March 2006
Available online 29 March 2006
Dedicated to Dr. Linda Glazer
Abstract—A novel experimental procedure for chemical reactions has been devised that involves mixing and then freezing the
reagents (organic solvent-free) to a sub-zero temperature such as À30 °C. This frozen mixture is exposed to microwave irradiation
for a brief period of time. The use of pre-cooled reagents may give a single product not obtained by traditional microwave irradi-
ation at room temperature. Interestingly, such a product may provide information about mechanisms by identifying the first step of
a multiple step reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
Microwave irradiation is a convenient procedure for
conducting reactions in minutes that otherwise would
require hours under traditional heating.1 Publications
that discuss microwave promoted chemistry appear
frequently; they record acceleration of diverse organic
reactions under microwave irradiation—starting at room
temperature and raising the temperature of the mixture
by about 30–100 °C.
the room temperature; it is then worked up in the usual
manner, and the organic product(s) is isolated.
These studies have led to the following observations:
1. Chemical reactions under microwave irradiation may
be modified by the temperature range of the irradia-
tion experiment. Identical reaction mixtures exposed
to microwaves at room temperature or at sub-zero
temperature (such as À30 °C) may give different
products (for example, 5- vs 3-nitro aromatic com-
pounds in nitration experiments); for additional
information, see Tables 1 and 2.
2. The ‘Cold Microwave Chemistry’ product (obtained
by microwave irradiation of pre-cooled reagents)
could provide information about reaction mechanism
since it might identify the first step in a reaction that
involves two or more steps.
Recent studies in our laboratory have led to a new
experimental strategy that we have named ‘Cold Micro-
wave Chemistry.’ Our approach involves cooling a mix-
ture of reagents—free of organic solvents—to a suitable
sub-zero temperature (such as À30 °C) with the help of a
cooling bath. The frozen mixture is exposed to micro-
wave irradiation (400–800 W) for approximately 2 min
in a domestic microwave oven (see Tables 1 and 2 for
details); it is our experience that this amount of micro-
wave exposure is adequate. The reaction mixture is
removed from the microwave oven and allowed to reach
It may be noted that the traditional microwave chemis-
try experiment involves placing a mixture of reagents
inside a microwave oven (in a sealed or open container)
and conducting irradiation at a selected power level for
a few minutes. Starting at room temp (20–25 °C), the
reaction mixture is subjected to a bulk temperature rise
of about 20–100 °C in the course of a few minutes to
obtain new products. In contrast, the experimental
approach for using ‘Cold Microwave Chemistry’
Keywords: Selective nitration reactions; Nitration of phenols; Micro-
wave assisted nitration reactions; Microwave irradiation of pre-cooled
reagents.
*
Corresponding author. Tel.: +1 610 258 8624; fax: +1 610 438
8232; e-mail: abose@stevens.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.059

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A. K. Bose et al. / Tetrahedron Letters 47 (2006) 3213–3215
Table 1. Nitration products of salicylaldehyde
Starting conditions
Microwave parameters
Melting point of
product (yield)
Structure of producta
CHO
OH
Room temp
Room temp
12 s, 400 W, max temp 85 °C
126 °Cb (62%)
(in Milestone Microwave Lab-station)
O2N
CHO
OH
1 min, 400 W, max temp 120 °C
68–71 °Cc (67%)
(in Milestone Microwave Lab-station)
O2N
CHO
NO2
OH
Cold temp (cooled in liquid nitrogen, À30 °C)
3 min, 500 W
(in Milestone Microwave Lab-station)
110 °Cd (65%)
NO2
a Characterized by GC–MS.
b Lit. mp 128–130 °C (Aldrich catalog).
c Lit. mp 68–70 °C (Aldrich catalog).
d Lit. mp 105–109 °C (Aldrich catalog).
Table 2. Nitration products of salicylic acid
Starting conditions
Room temp
Microwave parameters
Melting point of
product (yield)
Structure of producta
COOH
OH
2 min, 200 W, max temp 85 °C (in Milestone Microwave Lab-station)
1 min, 400 W, max temp 120 °C (in Milestone Microwave Lab-station)
228–229 °Cb (72%)
169–170 °Cc (76%)
O2N
COOH
OH
Room temp
O2N
NO2
a Characterized by GC–MS.
b Lit. mp 233–235 °C (Aldrich catalog).
c Lit. mp 169–172 °C (Aldrich catalog).
requires prior lowering of the temperature of the
reactants to a sub-zero level before microwave irradia-
tion.
A mixture of the starting compound 2 and nitric acid
(10%) was cooled to about À30 °C with a cooling bath
and the frozen mixture was exposed to low power
(300 W) microwave irradiation for a brief period of time
(about 2 min). The frozen reaction mixture was placed
outside the oven and allowed to warm up to the room
temperature; it was then worked up in the usual manner
and the organic product(s) was isolated. This product
was identified as 3—the result of ipso displacement of a
carboxy group by a nitro group.3 The yield was 90%.
Microwave promoted nitration of 3 with nitric acid
(10%) provided the dinitro compound 1—in 80% yield.
Recently we have studied the microwave promoted
preparation of an unusual dinitro natural product (1),
which we had isolated in milligram quantities from a
natural source.2 It was found that when a mixture of
4-hydroxycinnamic acid (2) and dilute nitric acid
(10%) was exposed to microwave irradiation for a few
minutes, the dinitro compound 1 was obtained in
80–90% yield.2 In an attempt to obtain the mononitro
analogues (3, 4), microwave irradiation was conducted
at about 0 °C, but only the dinitro product 1 was
formed.
These reactions clearly indicate the possibility of obtain-
ing different products from identical reaction mixtures
when the microwave irradiation is started at different
temperatures. As shown above, compound 3 or com-
pound 1 could be obtained selectively from compound
2 depending on whether the reagents were pre-cooled
or not. These experiments also show that the favored
pathway from 2 to 1 is via 3 and not via 4.
The conversion of 2 to the dinitro compound 1 involves
two chemical steps: (i) nitration of a phenol, (ii) ipso
replacement of a carboxy group by a nitro group. It
was possible to determine the sequence of these two
steps by a ‘Cold Microwave Chemistry’ experiment.

A. K. Bose et al. / Tetrahedron Letters 47 (2006) 3213–3215
3215
Acknowledgments
OH
OH
O2N
HOOC
We thank Union Mutual Foundation, Merck Company,
and The Camille and Henry Dreyfus Special Grant Pro-
gram in the Chemical Sciences for financial support. For
useful discussions and encouragement we are grateful to
Dr. F. T. Jones, Dr. Malcolm MacCoss, and Dr. Mark
Cardillo. We are indebted to the reviewer for valuable
suggestions.
2
3
4
OH
2
OH
2
HOOC
O2N
NO
NO
1
References and notes
Scheme 1.
1. (a) Loupy, A. Microwave in Organic Synthesis; Wiley-VCH:
Weinheim, 2002; (b) Kingston, H. M.; Haswell, S. J.
Microwave Enhanced Chemistry; American Chemical Soci-
ety Publications: Washington, 1997; (c) Tierney, J. P.;
Lidstrom, P. Microwave Assisted Organic Chemistry; CRC
Press: Boca Raton, 2005; (d) Kappe, C. Oliver; Stadler, A.
Microwaves in Organic and Medicinal Chemistry; C.H.I.P.S.
Books: Weimar, 2005.
The interrelations shown in Scheme 1 indicate the
sequence of steps leading to the dinitro compound. It is
interesting to note that the first step is the ipso decarb-
oxylation with replacement by a nitro group; nitration
of the phenolic ring is therefore the second step.
2. Bose, A. K.; Ganguly, S. N.; Manhas, M. S.; Srirajan, V.;
Bhattacharya, A.; Rumthao, S.; Sharma, A. Tetrahedron
Lett. 2004, 45, 1179.
The ‘Cold Microwave Chemistry’ approach could thus
allow easy determination of the first step in a reaction
involving two or more steps. These are novel aspects
of microwave enhanced reactions that do not appear
to have been reported before.
3. Experimental procedure: Cold microwave chemistry for the
nitration of 4-hydroxycinnamic acid: 4-Hydroxycinnamic
acid (2 g, 12 mmol) and aqueous nitric acid (20 mL, 10%
strength) in a 100 mL Erlenmeyer flask was cooled to
À30 °C with a liquid nitrogen bath. This frozen reaction
mixture was irradiated in an unmodified domestic micro-
wave oven at 300 W power for 30 s. Immediately after
irradiation, 75 mL of ice cold water was added with stirring.
An orange yellow solid that separated was collected by
filtration. The solid was washed with cold water until the
filtrate was acid free and then dried. It was crystallized from
methanol–ethyl acetate mixture to provide the mono-nitro
product 3 (1.8 g, 11 mmol), mp 204–205 °C, yield 90%. An
analytical sample was prepared by repeated crystallization.
In summary, chemical reactions under microwave irra-
diation may be modified by the starting temperature of
the irradiation experiment. For example, microwave
irradiation of identical reaction mixtures at room
temperature or pre-cooled to À30 °C may give different
products. The cold microwave chemistry product
(obtained by microwave irradiation of a pre-cooled
reagent mixture) may identify the first step in a reaction
that involves two or more steps; this could provide
useful information about reaction mechanisms and thus
supplement traditional studies involving reaction
kinetics. These microwave chemistry experiments can
be conducted in inexpensive domestic microwave (800–
1000 W) ovens.
1
IR (KBr): 3280, 1518, 1320, 976, and 825 cmÀ1. H NMR
(CDCl3, d): 7.58 (d, J = 13.7 Hz, 1H); 7.96 (d, J = 13.7 Hz,
1H); 7.42–8.09 (aromatic protons, 4H); 10.65 (s, chelated,
1H). Anal. Calcd for C8H7NO3: C, 58.18; H, 4.24; N, 8.48.
Found: C, 58.31; H, 4.22; N, 8.44.