The important role of solvent vapor in an organic solid state reaction

Article abstract of DOI:10.1039/b503922c

Some organic reactions in the solid state proceeded very efficiently and selectively in the presence of a small amount of solvent vapor. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503922c

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The important role of solvent vapor in an organic solid state reaction
Seiken Nakamatsu,a Shinji Toyota,a William Jonesb and Fumio Toda*a
Received (in Cambridge, UK) 17th March 2005, Accepted 3rd June 2005
First published as an Advance Article on the web 1st July 2005
DOI: 10.1039/b503922c
when the reaction in the solid state was carried out at room
temperature in the presence of MeOH vapor for 1 h the result was
3 in 63% yield.{ By prolongation of the reaction time to 2 and 4 h,
the yield increased to 81 and 90%, respectively. The efficiency
of these reactions under the MeOH vapor is much better than
that of the simple solid state reaction and the solution reaction
in MeOH (Table 1). Although MeCN is not as effective as
MeOH, it is still better than the reaction in the absence of
solvent vapor.
Some organic reactions in the solid state proceeded very
efficiently and selectively in the presence of a small amount of
solvent vapor.
It has been well established that some organic reactions proceed
efficiently and selectively in the solid state.1 However, some solid
state reactions proceed more slowly than solution reactions.
Recently, we found that some solid state reactions proceed very
efficiently and selectively in the presence of a small amount of
solvent vapor. Since only a small amount of solvent vapor is
sufficient for the acceleration of the reaction and increasing the
selectivity, this method is important from the viewpoint of green
and sustainable chemistry. Some phase transitions in the solid state
which are accelerated by a solvent vapor have been reported.2
However, organic solid state reactions which are accelerated by a
solvent vapor have never been reported. Some such examples of
the Michael and Br2 addition reactions in the solid state are
reported.
Addition reactions of Br2 to chalcone (4) were carried out by
keeping a mixture of powdered 4 and a pyridine?HBr?Br2 complex
(5) at room temperature under various conditions (Table 2). The
solid state reaction in the absence of solvent vapor for 4 h gave a
100 : 0 mixture of erythro- (6) and threo-addition products (7) in
72% yield. This result was better than that of the solution reaction
in CH2Cl2 which gave a 91 : 9 mixture of 6 and 7 in 62% yield. The
solid state reaction was also accelerated by various solvent vapors
and even water vapor played an important role as did organic
solvent vapors.
When a solution of 5,5-dimethylcyclohexane-1,3-dione (1) and
2,2-dicyano-p-chlorostyrene (2) in MeOH was kept at room
temperature for 1 h, the Michael addition reaction product 3 was
obtained in 71% yield (Table 1). In contrast, the reaction in the
solid state gave 3 in a poor yield. For example, heating a mixture
of 1 and 2 at 100 uC for 4 h gave 3 only in 21% yield. However,
In order to make the contact with solvent vapor efficient, the
solid state reaction of various chalcone derivatives 8 with 5 was
carried out in the presence of various solvent vapors by mixing
every hour with a spatula (Table 3). The efficiency and the
selectivity of all reactions were much better than those of the
corresponding solid state reactions in the absence of solvent vapor.
Finally, the satisfactory contact of the solvent vapor with 8 and 5
was found to be important. When the reaction of 8b with 5 in
Table 1 Michael reaction of 1 and 2 in the solid state at room
temperature in the absence and presence of solvent vapora
Table 2 Addition reaction of Br2 to 4 in the solid state at room
temperature in the absence and presence of solvent vapora
Conditions
Conditions
Products
Yield (%)
Solvent vapor
Reaction time/days
Yield of 3 (%)
Solvent vapor
Reaction time/h
6 : 7 Ratio
b
—
4
1
2
4
2
4
21
63
81
90
25
51
MeOH
MeOH
MeOH
MeCN
MeCN
a
—
4
1
2
1
2
2
4
4
2
4
72
95
82
94
88
81
95
73
93
71
100 : 0
99 : 1
100 : 0
98 : 2
100 : 0
99 : 1
95 : 5
100 : 0
100 : 0
100 : 0
CH2Cl2
MeCN
CHCl3
MeOH
EtOH
benzene
H2O
When the reaction was carried out in MeOH solution for 1 h, 3
was obtained in 71% yield. Reaction was carried out at 100 uC.
b
Et2O
Hexane
a
aDepartment of Chemistry, Faculty of Science, Okayama University of
Science, Ridaicho 1-1, Okayama 700-0005, Japan.
E-mail: toda@chem.ous.ac.jp; Fax: 81 86 256 9604; Tel: 81 86 256 9604.
bDepartment of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW
When the reaction was carried out in CH2Cl2 and MeCN solution
for 1 h, 6 and 7 were obtained in 62 (91 : 9) and 67% (100 : 0)
yields, respectively, in the 6:7 ratios indicated.
3808 | Chem. Commun., 2005, 3808–3810
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The efficiency of the solid state reaction in the presence and
absence of CH2Cl2 vapor was compared by monitoring the
reaction by IR spectral measurements (Fig. 1). In the presence of
CH2Cl2 vapor, as the reaction proceeds, nCLO of 11 at 1650 cm21
decreased and almost disappeared after 1 h and nCLO at
1670 cm21 of the product increased. Since the amount of
CH2Cl2 vapor is very small, its absorption did not appear in the
spectra. In the latter, however, no significant change occurred after
30 and 60 min.
Table 3 Addition reaction of Br2 to 8 in the solid state at room
temperature in the absence and presence of solvent vapora
Conditions
Products
Yield (%)
Solvent vapor
Reaction time/h
9 : 10 Ratio
In some cases, however, solvent vapor retarded the solid state
reaction. For example, when the reaction of (E)-stilbene (14) and 5
was carried out under solvent vapor at room temperature it gave
the pure trans-addition product (15) in the yields indicated
(Table 5). These yields are lower than those by the solid state
reaction in the absence of the solvent vapor. Nevertheless, all these
solid state reactions gave the meso-isomer (15) as the sole product,
but not any rac-isomer (16), although the solution reaction in
CH2Cl2 for 16 h gave a 97 : 3 mixture of 15 and 16 in 76% yield.
Nevertheless, when the complex PhN+Me3?Br2?Br2 (17) is used as
a reagent instead of 5 for the bromination reaction of 14 in the
presence of CH2Cl2 vapor, 15 was obtained selectively in 96%
yield, although the reaction in the absence of CH2Cl2 vapor gave
15 in 49% yield (Table 5).
8a
8b
8c
8d
a
—
CH2Cl2
—
CH2Cl2
—
CH2Cl2
—
CH2Cl2
3
3
3
3
2
2
2
6
9
85
4
93
6
87
0
70
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
93 : 7
All reactions were carried out by mixing every one hour by
spatula.
CH2Cl2 was carried out at room temperature for 3 h, a mixture of
9b and 10b (93 : 7 ratio) was obtained in 69% yield. These data
again support that the solid state reaction in the presence of
solvent vapor has many advantages.
The reaction of (E)-dibenzoylethylene (11) and 5 which gives a
mixture of meso- (12) and rac-addition products (13), also
proceeded efficiently and selectively in the presence of solvent
vapor. When a solution reaction of 11 and 5 was carried out in
CH2Cl2 for 2 h, a 50 : 50 mixture of 12 and 13 was obtained in
73% yield. Although the selectivity increased to 83 : 17 when the
reaction was carried out in the solid state for 20 h, the yield was
only 38%. In contrast, the yield and the selectivity were improved
by carrying out the solid state reaction under CH2Cl2 vapor and a
89 : 11 mixture of 12 and 13 was obtained in 88% yield (Table 4).
Nevertheless, MeOH and EtOH vapor was not as effective as
CH2Cl2 vapor (Table 4). Such a difference is also observed
sometimes in solution reactions as a solvent effect. The possibility
that the difference depends on the solubility of the Br2 generated
from 5 in the solvent used can be neglected, since Br2 is freely
soluble in all these solvents. However, it is not clear whether the
solvent effect in the solution reaction is similar or not to that in the
solid state reaction.
Fig. 1 Monitoring of the solid state reaction of 11 with 5 in the presence
(A) and absence (B) of CH2Cl2 vapor by the ATR method.
Table 5 Addition reaction of Br2 to 14 in the solid state at room
temperature in the absence and presence of solvent vapora
Table 4 Addition reaction of Br2 to 11 in the solid state at room
temperature in the absence and presence of solvent vapora
Conditions
Products
Reagent Solvent vapor Reaction time (h) Yield/% 15 : 16 Ratio
Conditions
Products
Yield (%)
5
5
5
5
5
—
48
48
18
18
18
24
16
68
36
31
41
40
49
96
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
CH2Cl2
MeOH
EtOH
MeCN
—
Solvent vapor
Reaction time/h
12 : 13 Ratio
—
20
2
2
38
88
34
36
83 : 17
89 : 11
88 : 12
91 : 9
CH2Cl2
MeOH
EtOH
a
17
17
a
CH2Cl2
2
When the reaction was carried out in CH2Cl2 for 16 h, a 97:3
When the reaction was carried out in CH2Cl2 for 2 h, a 50 : 50
mixture of 15 and 16 was obtained in 76% yield.
mixture of 12 and 13 was obtained in 73% yield.
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intramolecular hydrogen bonded OH groups, respectively.5 After
10 min, new inter- and intramolecular hydrogen bonded nOD
absorptions of deuterated 18 appeared at 2579 and 2526 cm21
,
respectively. After 120 min, about a half of the molecules of 17
were deuterated (Fig. 2).
These data show that MeOD vapor comes into the crystal of 17
and H–D exchange occurs easily. Finally, it is reasonable to
consider that solvent vapor comes into the crystal of the reactant
together with the reagent molecule and solid state reaction occurs
efficiently. It is also probable that some solvent vapors come into
the crystal easily and some do so with difficulty.
Fig. 2 Monitoring by the ATR method at room temperature of the
deuterium exchange reaction between powdered 17 and MeOD vapor.
The authors acknowledge Mr. Shinya Hirano of Okayama
University of Science for his technical assistance. The authors
also acknowledge financial support from MEXT.HAITEKU
(2001–2005).
All the solid state reactions under solvent vapor atmosphere
were carried out in a sealed flask filled with air and solvent vapor.
For example, when a mixture of 4 or 11 and an equimolar amount
of 5 was kept in a sealed flask filled with air and a 0.4 mmol
amount of CH2Cl2 vapor at room temperature for 1 h, 6 and 7 in a
99 : 1 ratio (95% yield), and 12 and 13 in a 89 : 11 ratio (88% yield)
were obtained after recrystallization in the yields indicated,
respectively. In a previous paper, we reported that co-crystal-
lization by grinding in the solid state is accelerated by addition of a
small amount of solvent.3 However, it is very interesting that a
small amount of solvent vapor accelerates the solid state reaction
and increases its selectivity.
Notes and references
{ Experimental details: All solid state reactions under solvent vapor
atmosphere were carried out in a sealed flask filled with air and solvent
vapor roughly in a 1 : 1.2 : 0.25 molar ratio of reactant : reagent : solvent
vapor. For example, a mixture of powdered 4 (200 mg, 0.96 mmol), and 5
(369 mg, 1.15 mmol) was kept in a flask (2 ml volume) filled with CH2Cl2
vapor (20 mg, 0.24 mmol) for 1 h. The reaction product was washed with
aqueous Na2S2O3 to give the product (336 mg, 95%) as a mixture of 6 and
7 in a 99 : 1 ratio. All the ratios of isomers were determined by 1H NMR
spectra.
It has been well established that gas–solid reactions proceed
efficiently, and mechanistic studies of these reactions have been
carried out by Kaupp and his co-workers using AFM techniques.4
However, the AFM technique is available only to study the surface
reaction of the solid. In order to clarify the mechanism of the
important role of the solvent vapor in the organic solid state
reaction, we studied how the solvent molecule easily comes into the
crystal. Powdered rac-2,29-dihydroxy-1,19-binaphthyl (17) is
exposed to MeOD vapor at room temperature and deuteration
of the OH group of 17 was monitored by measurement of IR
spectra in the solid state (Fig. 2). At the beginning of the
measurement, only the nOH absorptions of 17 appeared at 3485
and 3402 cm21, which have been assigned to inter- and
1 F. Toda, Top. Curr. Chem., 1988, 149, 211; F. Toda, Top. Curr. Chem.,
2005, 254, 1; F. Toda, Synlett, 1993, 303; F. Toda, Acc. Chem. Res., 1995,
28, 480; K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1025; K. Tanaka
and F. Toda, Thermal Organic Reactions in the Solid State, in Organic
Solid-State Reactions, ed. F. Toda, Kluwer Academic Publishers,
Dordrecht, 2002, p. 109; Z. Urbanczyk-Lipkowska, Selective Reactions
in Inclusion Crystals in Organic Supramolecular Chemistry, ed. F. Toda
and R. Bishop, John Wiley & Sons, Ltd., New York, 2004, p. 173.
2 K. Yoshizawa, S. Toyota and F. Toda, Chem. Commun., 2004, 1844;
K. Yoshizawa, S. Toyota and F. Toda, Tetrahedron, 2004, 60, 7767.
3 N. Shan, F. Toda and W. Jones, Chem. Commun., 2002, 2374.
4 G. Kaupp, Top. Curr. Chem., 2005, 254, 95.
5 F. Toda, K. Tanaka, H. Miyamoto, H. Koshima, I. Miyahara and
K. Hirotsu, J. Chem. Soc., Perkin Trans. 2, 1997, 1877.
3810 | Chem. Commun., 2005, 3808–3810
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