Selective formation of glycylglycine by dehydration of glycine adsorbed on silica gel

Article abstract of DOI:10.1002/(SICI)1099-1395(199904)12:4<354::AID-POC157>3.0.CO;2-D

Silica gel promotes the selective dehydration of glycine to form intermediate glycylglycine, with inhibition of the formation of stable glycine anhydride and polymer products. IR measurements indicate that glycine adsorbed on silica gel results in the formation of neutral species having C=O and NH₂ groups. The species is considered to stimulate dehydration, leading to the reported selective dehydration. Copyright

Full text of DOI:10.1002/(SICI)1099-1395(199904)12:4<354::AID-POC157>3.0.CO;2-D

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 12, 354–356 (1999)
Short Communication
Selective formation of glycylglycine by dehydration of
glycine adsorbed on silica gel
Haruo Ogawa,1* Tamiki Fujigaki1 and Teiji Chihara2
1Department of Chemistry, Tokyo Gakugei University, Koganei, Tokyo 184-0015, Japan
2Institute of Physical and Chemical Research (RIKEN), Wako, Saitama 351-0198, Japan
Received 9 October 1998; revised 21 December 1998; accepted 26 December 1998
ABSTRACT: Silica gel promotes the selective dehydration of glycine to form intermediate glycylglycine, with
inhibition of the formation of stable glycine anhydride and polymer products. IR measurements indicate that glycine
adsorbed on silica gel results in the formation of neutral species having C=O and NH2 groups. The species is
considered to stimulate dehydration, leading to the reported selective dehydration. Copyright 1999 John Wiley &
Sons, Ltd.
KEYWORDS: glycylglycine; glycine; dehydration; silica gel
Scheme 1
The application of solid adsorbents such as silica gel and
alumina as solid supports in organic synthesis affords a
new procedure for selective reactions, where substrates
are adsorbed and oriented on the surface of adsorbents
with suppression of translational movement.1 The
significant potential of adsorbents is highlighted in
selective organic transformations involving oxidation,2
alkylation,3 condensation,4 acetylation,5 monoetherifica-
tion6 and monomethyl esterification.7 Generally, dehy-
dration of amino acids proceeds both consecutively and
simultaneously, and consequently affords lactam and
polymer products. We have reported the selective
formation of "-caprolactam from 6-aminocaproic acid
using silica gel to suppress the formation of polymer
products.8 Generally, direct synthesis of intermediate
glycylglycine (GlyGly) from glycine (Gly) is not readily
achieved because of the subsequent ease of intramolecu-
lar or intermolecular dehydration from intermediate
GlyGly, consequently forming glycine anhydride (Gly
A) or the polymer products, respectively. It has been
reported that Gly A is formed from Gly in a solution
using metal alkoxides such as titanium isopropoxide.9
We report here the selective formation of intermediate
GlyGly from Gly using silica gel as the solid support.
Dehydration of Gly adsorbed on silica gel was
achieved using the following method (adsorption
method): silica gel (C-200, Wako, 10 g) was added to
an N,N-dimethylformamide (DMF) or water solution
containing a predetermined amount of Gly, and the
solvent was subsequently removed under reduced
pressure. The solid obtained (adsorption sample) was
*Correspondence to: H. Ogawa, Department of Chemistry, Tokyo
Gakugei University, Koganei, Tokyo 184-0015, Japan.
Copyright 1999 John Wiley & Sons, Ltd.
CCC 0894–3230/99/040354–03 $17.50

SELECTIVE FORMATION OF GLYCYLGLYCINE
Table 1. Selective dehydration of Gly to GlyGlya
355
Yield (%)
Amount of Gly
1
Method
(10 4 mol g SiO2)
Intact Gly (%)
GlyGly
Gly A
Selectivityb (%)
Adsorption
0.066
0.066
0.066
0.21
0.66
2.7
0.0
63.9
17.9
0.0
0.0
0.0
0.0
92.4
29.2
15.9
29.2
10.7
2.3
0.0
0.0
0.0
35.2
44.3
34.6
3.6
92.4
80.7
19.4
29.2
10.7
2.3
Adsorptionc
Adsorptiond
Adsorption
Adsorption
Adsorption
Homogeneouse
Homogeneousf
—
2.4
2.4
—
0.0
0.0
22.6
0.0
a
Each experiment was carried out under reflux in toluene for 20 h.
The value of [yield of the GlyGly/(100 intact Gly)] Â 100.
In the absence of toluene solvent at room temperature.
In the absence of toluene solvent at 100°C.
b
c
d
e
0.022 M solution of Gly in ethylene glycol under reflux.
f 0.20 M solution of Gly in ethylene glycol under reflux.
added to toluene (10–50 ml) and heated under reflux for
20 h using a Dean–Stark trap to collect the water formed
in the reaction. A reaction period of 20 h was sufficient
for completion of the reaction. After the reaction the
mixture was filtered and the solid was thoroughly washed
with distilled water and DMF. The combined washings
and filtrate were evaporated to low volume (in vacuo) and
the products were analyzed by gas–liquid chromatogra-
phy with a Yanagimoto Model G2800F gas chromato-
graph equipped with Unisol 30T column (0.5 m) and
high-performance liquid chromatography with a Tokyo-
Rikakikai EYELA PLC-10 system equipped with a TR-
35-415F(ODS) column (15 cm) using water as the eluent.
Butane-1,4-diol or higher alkanes were used as standards
for quantitative analysis.
The results of the dehydration are given in Table 1.
According to the adsorption method, the product GlyGly
was readily obtained in 92.4% yield with the adsorption
sample (6.6 Â 10 6 mol g 1, ꢀ = 0.0025). The selectivity
for the formation of GlyGly increases with decrease in
the amount of adsorbed Gly, suppressing the formation of
Gly A and polymer products. Significant yields of Gly A
were attained with higher loadings. In the absence of
toluene as solvent at room temperature, 80.7% of the
selectivity was achieved, but the reactivity of Gly was
suppressed, as illustrated by the remains of significant
quantities of unreacted Gly (63.9%). When the reaction
temperature was at 100°C, the reactivity increased with
intact Gly (17.9%), but the selectivity decreased
drastically, and only a 15.9% yield of GlyGly was
obtained. Under homogeneous conditions, lower selec-
tivities were recorded, and a 22.6% yield of Gly A was
obtained in a 0.20 M solution of Gly. In a 0.022 M
solution, only a 2.4% yield of GlyGly was obtained.
The IR absorption of Gly adsorbed on silica gel was
measured by Fourier transform IR spectrometry with a
JASCO FT/IR-7000 infrared spectrometer by the diffuse
reflection technique. Spectra including the absorption of
Figure 1. IR absorption of Gly on silica gel
authentic samples are illustrated in Fig. 1. Authentic
samples of Gly, GlyGly and Gly A were all guaranteed
grade from Tokyo-Kasei. The spectrum of authentic Gly
in the solid state was very complicated, but it exhibited
the characteristic bands at ca 1600–1560 cm 1 due to the
stretching vibration of carboxylate anion [ꢁasCO2 1
(as = asymmetric vibration)] and at ca 2900–2500 cm
due to ꢁNH3 .
‡ 10 Similarly, the spectrum of Gly adsorbed
on silica gel was also complicated, but notable differ-
Copyright 1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 354–356 (1999)

356
H. OGAWA, T. FUJIGAKI AND T. CHIHARA
amount required for complete surface coverage could be
estimated as 2.7 Â 10 3 mol g 1 on the basis of the cross-
1
sectional area of Gly (ca 0.23 nm2 molecule
by
molecular modelling) and the specific surface area of
silica gel (371 m2 g 1) by BET measurement. These data
imply that a decrease in the amount of Gly on silica gel
allows easier dispersion of Gly molecules on the silica gel
surface, thus suppressing intermolecular interactions
between Gly molecules. This resulted in Gly being
adsorbed predominantly as neutral species having C=O
and NH2 groups. This species is considered to promote
the dehydration of Gly readily, and the selective
formation of intermediate GlyGly is believed to be
achieved with the suppression of intermolecular inter-
actions between GlyGly molecules.
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Figure 2. IR absorption of Gly at various loadings
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1
ences existed, including new bands at 1700–1630 cm
due to the ꢁC O stretching vibration together with the
=
disappearance of the characteristic CO2 absorption as
seen with Gly in the solid state. Slight differences also
existed in the absorption intensities of the bands at ca
3400–3200 and ca 2900–2500 cm due to ꢁNH2 and
ꢁNH3 , respectively, i.e. an increase in intensity of ꢁNH2
1
‡
‡
was observed with a decrease in that of ꢁNH3
.
IR spectra of Gly on various loadings are illustrated in
Fig. 2. Changes in the spectra were observed with a
decrease in the amount of Gly, where the intensity of the
absorption of ꢁC=O increased with a simultaneous
decrease in that of ꢁasCO2 (spectra d–a, Fig. 2). This
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species having a C=O group. At fairly high loadings
3
1
(more than 2.7 Â 10
mol g
SiO2, ꢀ > 1.0), the
spectra were similar to that of Gly in the solid state. The
Copyright 1999 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 12, 354–356 (1999)