In situ DRIFTS study on the synthesis of N-alkylmorpholines

Article abstract of DOI:10.1007/s11164-012-0801-9

In situ diffuse reflectance Fourier-transform infrared spectroscopy was used to perform mechanistic investigation on the synthesis of N-alkylmorpholines from diethylene glycol (DEG), alcohol and ammonia. The results showed that the synthesis of N-alkylmorpholines on a heterogeneous catalyst proceeded along the reaction path between DEG and alkylamine when choosing CuO-NiO/γ-Al ₂O₃ as a suitable catalyst. In addition, the yield of methylmorpholine and ethylmorpholine was 86.4 and 76.6 %, respectively.

Full text of DOI:10.1007/s11164-012-0801-9

Res Chem Intermed (2013) 39:2825–2835
DOI 10.1007/s11164-012-0801-9
In situ DRIFTS study on the synthesis
of N-alkylmorpholines
•
Chenxi Luo Hu Luo Chao Qian Yunbin Chen
•
•
•
•
Lie Feng Xinzhi Chen
Received: 4 May 2012 / Accepted: 31 August 2012 / Published online: 18 September 2012
Ó Springer Science+Business Media B.V. 2012
Abstract In situ diffuse reflectance Fourier-transform infrared spectroscopy was
used to perform mechanistic investigation on the synthesis of N-alkylmorpholines
from diethylene glycol (DEG), alcohol and ammonia. The results showed that the
synthesis of N-alkylmorpholines on a heterogeneous catalyst proceeded along the
reaction path between DEG and alkylamine when choosing CuO–NiO/c-Al2O3 as a
suitable catalyst. In addition, the yield of methylmorpholine and ethylmorpholine
was 86.4 and 76.6 %, respectively.
Keywords In situ DRIFTS ꢀ N-alkylmorpholines ꢀ Mechanism ꢀ Synthesis
Introduction
N-Alkylmorpholines play an important role in the production of many chemical
compounds including surfactants, dyes, pesticides, preservatives, herbicides, rub-
ber accelerator, lubricants and medicinal intermediates [1–3]. For example,
N-alkylmorpholines can be used as important blocks in many pharmaceutical
compounds such as moclobemide for depression, fominoben for antitussive,
morphocycline for infection and the diagnosis of lung cancer, bimolane for
psoriasis, and so on (Fig. 1). Given its versatility, exploring more efficient synthesis
of N-alkylmorpholines is still attracting much attention [4, 5].
There are two main methods of synthesizing N-alkylmorpholine. A traditional
method is substitution on morpholine with alkyl halides, which is efficient but
C. Luo ꢀ H. Luo ꢀ C. Qian ꢀ X. Chen (&)
Department of Chemical and Biological Engineering, Zhejiang University,
Hangzhou 310027, People’s Republic of China
e-mail: eric8948@163.com; xzchen@zju.edu.cn
Y. Chen ꢀ L. Feng
Zhejiang Jianye Chemical Co., Ltd., Jiande 311600, People’s Republic of China
123

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C. Luo et al.
Cl
O
O
OH
O
N
N
H
Cl
HO
O
N
N
O
H
H
N
OH
O
O
HN
O
OH
N
O
N
N
O
N
N
HO
HN
N
O
O
O
N
O
moclobemide
fominoben
morphocycline
bimolane
Fig. 1 N-Alkylmorpholines used as important blocks in pharmaceutical compounds
limited by involving mutagenic halides and much effluent. Moreover, polyalkylation
decreases the selectivity [6]. In response, metal-catalysed alkylation of amines with
alcohols was developed recently, which employs DEG, alcohol and ammonia as the
starting materials. Although the mechanism of synthesis of morpholine(III) has been
reported, the mechanism of synthesis of N-alkylmorpholines remains unknown [7, 8].
Considering that the monoalkylated products can be obtained with high selectivity
and that the approach is of less pollution [9], investigation on the mechanism of
synthesis of N-alkylmorpholines from alcohol, ammonia and DEG is of significant
importance. In this work, CuO–NiO/c-Al2O3 [10, 11] was used as catalyst, and a
mechanism of synthesizing N-alkylmorpholines was proposed on referring previous
mechanism of synthesis of morpholine through the study of the mechanism of
synthesis of methylmorpholine and ethylmorpholine (Schemes 1, 2, 3).
In situ diffuse reflectance Fourier transform infrared spectroscopy (DRIFTS) was
used to explore the mechanism of synthesis of N-alkylmorpholines from DEG(IV),
alcohol and ammonia. Because of its high sensitivity to surface species [12], the in
situ DRIFTS is a powerful tool for the investigation of adsorbed species and active
sites [13, 14]. This technique was frequently used in investigating the active sites,
Scheme 1 Improved synthesis of morpholine(III)
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In situ DRIFTS study on the synthesis of N-alkylmorpholines
2827
Scheme 2 Improved synthesis of methylmorpholine(I)
Scheme 3 Improved synthesis of ethylmorpholine(II)
the adsorbed species and the intermediates on the catalyst surface under reaction
conditions [15, 16]
Theoretical
Diffuse reflectance infrared obeys the Kubelka–Munk theory. While most quanti-
tative analysis assumes that the sample is infinitely thick, so the Kubelka–Munk
equation can be simplified as:
2
ð1 ꢁ R1Þ
2R1
k
s
fðR1Þ ¼
¼
k ¼ 2:303ec
where f(R?) is the function of K–M, R? represents the reflectivity of the infinite
thick sample, k represents the molar absorption coefficient of the sample, s repre-
sents the scattering coefficient of the sample, e represents molar absorption rate of
the sample, and c represents the molar concentration of the sample. It can be seen
from the equation that the function of K–M is proportional to c (the molar con-
centration of the sample), which provides a basis for quantitative analysis of diffuse
reflectance infrared.
Experimental
Catalyst preparation
CuO–NiO/c-Al2O3 was prepared using an impregnation method in a proper Cu/Ni
ratio. Firstly, the nitrates aqueous was prepared with Cu and Ni concentration of
17.1 wt.% and 4.3 wt.%, respectively. Secondly, the support, c-Al2O3
(SBET = 220 * 250m2g-1, U = 2 * 3 mm) was calcined at 450 °C for 3 h and
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C. Luo et al.
850 °C for 6 h in a muffle furnace, then dipped in the nitrates aqueous for 36 h, and
the decrement of water volume was measured to determine the pore volume. The
measured pore volume density of the calcined c-Al2O3 was 0.9 mL g-1. Then,
4.26 g of Ni(NO3)2ꢀ6H2O, 12.91 g of Cu(NO3)2ꢀ3H2O and 12 g of H2O were
formulated into a solution. In addition, the 15.72 g of calcined c-Al2O3 was
impregnated with the above-mentioned solution for sufficient time for the solution
to be absorbed completely, and dried at 60 °C for 3 h under stirring, and then the
filtered catalyst was calcined at 280 °C for 6 h, and cooled to room temperature (the
suitable volume of carrier was selected in order to ensure that its pore volume was
equal to that of the above-mentioned solution). The specific surface area of the
compounds was 178.7 m2 g-1, the pore volume was 0.36 mL g-1 and the pore
diameter was 17.2 nm.
In situ DRIFTS procedure
As shown in Fig. 2, the in situ DRIFTS spectra were recorded on a Nicolet
5700-FTIR (Fourier transform infrared) equipped with a MCT/A detector cooled by
liquid N2. A gas-handling system was connected to a Spectra-Tech0030-91 high
temperature high pressure reaction cell in situ with ZnSe windows, light
transmission range of 5,000–500 cm-1. All spectra were measured with a resolution
of 8 cm-1 and an accumulation of 64 scans. All gas mixtures were fed at a flow rate
of 15–25 mL min-1 controlled by Brooks 5850E mass flow meter (MFC).
A CN8500-type temperature control unit was used for heating and temperature
control accuracy of 1 °C; the maximum temperature was 900 °C.
At the start, 1.5 g CuO–NiO/c-Al2O3 was placed in a ceramic crucible. Prior to
each experiment, the valves of V2 and V4 were opened while the others remained
Fig. 2 Diffuse experimental setup
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In situ DRIFTS study on the synthesis of N-alkylmorpholines
2829
closed. The catalyst was first heated in a flow of 15 mL min-1 H2 for 60 min at
513 K until the infrared absorption signal remained stable, which showed that the
activation of the catalyst was completed. Second, the temperature of the ceramic
crucible was adjusted to the desired temperature of the reaction. Then, the
temperature, atmospheric pressure, the flow of 15 mL min-1 H2 and a desired
spectrum of the catalyst in the flow of H2 serving as the background were recorded.
Finally, the valves of V1, V3 and V5 were opened, then the raw materials such as
DEG(IV) and alcohols were bubbled into the ceramic crucible by hydrogen and
reacted with NH3; hydrogen was used to protect and activate the catalyst. At the
same time, recording IR data was begun based on the background spectrum.
The reaction mixtures were analyzed by gas chromatography [Agilent 1790F
fitted with a flame ionization detector (FID) and a SE-30 column (50 cm long);
Nanjing Xuxi Apparatus, China) and GC–MS (TRACE G2000/TRACE MS;
ThermoQuest, USA] by comparing with the standard sample when nitrogen was
used as carrier gas. The GC conditions are shown in Table 1. The yields were
determined by an external standard method. To begin with, nine different arithmetic
concentration standard samples were prepared around the probable concentration of
the analyte. Secondly, the samples were analyzed by GC at the same injection
volume. Additionally, a scatter diagram was drawn with the concentration of the
standard sample as the x axis and the peak area as the y axis, and a linear regression
was made. Finally, the reaction mixture was analyzed by GC at the same injection
volume as the standard samples, and the concentration was calculated on basis of
the peak area by comparing with the scatter diagram.
Results and discussion
Catalyst activity test
The synthesis of N-alkylmorpholines from DEG(IV), methanol and ammonia in
gas–solid phase was investigated in a fixed-bed reactor over CuO–NiO/c-Al2O3.
The reaction was efficient for primary alcohols with high conversion and selectivity
under optimum conditions. The results showed that CuO–NiO/c-Al2O3 was a
suitable catalyst for the synthesis of N-alkylmorpholines (Table 2).
Effect of the different carrier and gas flow on the reaction
Because of its dark brown color, the CuO-NiO/c-Al2O3 used in the experiment has a
strong absorption of infrared radiation, combined with the weak diffuse reflectance
Table 1 The GC conditions
Column head
pressure (MPa)
Column
temperature
(°C)
FID detector with
temperature (°C)
Inlet
temperature
(°C)
Column heating rate
(°C min-1
)
0.1
260
260
100
20
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C. Luo et al.
Table 2 The results of the synthesis of N-alkylmorpholines
Target product
Molar ratio
Temperature Hydrogen LHSVa(h-1
)
Conversion
(%)
Selectivity
(%)
(oC)
pressure
(MPa)
Methylmorpholine (DEG):(methanol):
220–225
220–225
1.0
0.9
0.25
0.25
99.4
98.5
86.9
77.8
(ammonia) = 1:1:6
Ethylmorpholine
(DEG):(ethanol):
(ammonia) = 1:1:6
a
ðhꢁ1
Þ
Volume flow of raw materials
Volume of catalyst
LHSV represents the liquid hourly space velocity, LHSV ¼
infrared signal. The infrared absorption signal becomes so weak that it is necessary
to add an appropriate carrier to dilute the catalyst. However, the absorption peak
signal of the catalyst which contained Al2O3 is stronger and more informative than
KBr, so Al2O3 is superior as the catalyst carrier.
In addition, determining a reasonable gas flow is all-important. Excessive gas
flow will blow the sample powder into the pipe, causing two negative effects: the
pipe will be blocked, and the spectral quality will be lowered as the surface of the
catalyst is uneven. After a series of tests, the total gas flow was fixed to
15*25 mL min-1, in which H2 flow is 15 mL min-1. The total gas flow was
controlled by adjusting the NH3 flow.
The mechanism of the synthesis of morpholine(III)
In the en suite DRIFTS spectrum of the synthesis of morpholine(III) from DEG(IV)
and ammonia (as shown in Fig. 3), the presence of bands in difference spectra at
around 3338, 1740, 1710, 1635, 1550 and 1510 cm-1 can be observed (Table 3).
The sharp and single peak at 3,338 cm-1 is attributed to –N–H, therefore the
reaction between C and E (Scheme 4) were rapid and the sharp peak was attributed
to the compounds D, G and I. The pair bands at 1,740 and 1,710 cm-1 are attributed
to the aldehyde B and F, whereas the bands are so small that sometimes they are
unable to identify. Thus it can be concluded that the intermediate is unstable and
prone to convert to the product. Adsorption of C=N (D and H) lead to the
appearance of a large and stable band at 1,635 cm-1 which is attributed to the
imine. The result indicated that the presence of the imine intermediate (D and H) is
stable during catalytic amination of alcohol. The dehydrogenation, amination and
dehydration are rapid while the hydrogenation of imine is slow. In addition, a
double peak at 1,550 and 1,510 cm-1 is attributed to the carbon deposition. The size
of the absorption peak increased with the reaction time and the temperature (the
carbon deposition was formed mainly by two ways, one was the solid carbon
enrichment generated through the condensation and dehydrogenation process from
hydrocarbons as raw materials. The other was the carbon decomposed from the
hydrocarbons directly or the carbon and light hydrocarbons generated through the
interaction between reactant and catalyst surface. The phenomenon of carbon
deposition has been proved by TGA).
123

In situ DRIFTS study on the synthesis of N-alkylmorpholines
2831
Deriving the mechanism of the synthesis of morpholine(III) from the above
analysis:
As C=O (1740, 1710 cm-1) was detected by IR Spectra, aldehyde B was
generated through the dehydrogenation reaction from DEG(A) over CuO–NiO/c-
Al2O3. Secondly, C was generated through the addition reaction from ammonia and
aldehyde B. Adsorption of C=N (1,635 cm-1) and N–H (3,338 cm-1) is attributed
to the imine D, which was generated through the dehydration–elimination reaction
from intermediate C. In addition, after a series of hydrogenation, dehydrogenation
and cyclization reactions, secondary amines G (N–H 3,338 cm-1) was generated
from imine D, which generated imine H (C=N 1,635 cm-1) through the
dehydration–elimination reaction. Finally, morpholine I (N–H 3,338 cm-1) was
generated through the hydrogenation reaction from imine H and hydrogen.
The mechanism of the synthesis of N-alkylmorpholines
There are two possible routes in the synthesis of N-alkylmorpholines from
DEG(IV), alcohol and ammonia. One route proceeds along the path of the reaction
between DEG(IV) and alkylamine, and the other is along that between morpho-
line(III) and alcohol. If the reaction route is the latter one, the spectrum of the
synthesis of methylmorpholine(II) from DEG(IV) and methanol should be similar to
that of the reaction between morpholine(III) and methanol (Fig. 4), but different
from that of the reaction between DEG(IV) and methylamine. However, from
Fig. 5, it can be seen that a sharp peak appeared at 3,338 cm-1, and a large and
stable band at 1,635 cm-1, which are all attributed to amine. Further, the additional
band at 3,440 cm-1 that is attributed to the generated hydroxyl in the reaction
between morpholine(III) and methanol is not the character of the reaction between
DEG(IV), alcohol and ammonia (Fig. 5). Actually, they were just the character of
the reaction between morpholine(III) and methanol (Fig. 4). Compared with the
t=30min
t=25min
t=20min
t=15min
t=10min
4000
3500
3000
2500 2000
wavenumbers/cm
1500
1000
-1
Fig. 3 The in suit DRIFTS spectrum of the synthesis of the morpholine(III) from DEG(IV) and ammonia
varies with the reaction time at 220 °C
123

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C. Luo et al.
Table 3 The presented information from Fig. 3
t/cm-1a Functional group
Type
3,338
3,230
N–H
O–H
C–H
C=O
Attributed to the intermediate products (secondary
amines)
The hydroxyl of DEG and the intermediate
products
2,944,
2,864
The C–H stretching vibration of methyl and
methylene
1,740,
1,710
Attributed to the intermediate products (aldehyde)
1,635
1,380
C=N
C–H
Attributed to the intermediate
The C–H bending vibration of methyl and
methylene
1,280
C–O
C–O
Attributed to the alkyl ethers
1,080,
1,050
Attributed to the hydroxyl of DEG and the
intermediate products
980,
915
=C–H
The out-plane bending vibration of =C–H,
attributed to the intermediate products (imine)
1,550
1,510
a
The unsaturated hydrocarbons of high
carbon hydrogen ratio
Stay on the catalyst’s surface because of the
carbon deposition
The unsaturated hydrocarbons of low
carbon hydrogen ratio
Stay on the catalyst’s surface because of the
carbon deposition
t/cm-1 = the frequency of the absorption peak
Scheme 4 The mechanism of the synthesis of morpholine(III) from DEG(IV) and ammonia
single band at 3,338 cm-1 (Fig. 3), the trend of the doublet at 3,338 cm-1 and
3,230 cm-1 (Fig. 3) was strengthened, which was attributed to the increasing of the
absorption bands of primary amine. From Fig. 5, it can be seen that the peak
appeared in the spectra at 1,635 cm-1 attributed to the imine becoming smaller. The
reason was that, in the synthesis of morpholine, both amination processes generated
imine. On the other hand, only the reaction between methylamine and DEG
generated imine in the synthesis of N-alkylmorpholines, and the subsequent
123

In situ DRIFTS study on the synthesis of N-alkylmorpholines
2833
t=30min
t=25min
t=20min
t=15min
t=10min
4000
3500
3000
2500 2000
1500
1000
wavenumbers/cm-1
Fig. 4 The in situ DRIFTS spectrum of the synthesis of methylmorpholine(II) from morpholine(III) and
methanol varies with the reaction time at 220 °C
Morpholine
Methyl-
morpholine
Ethyl-
morpholine
4000
3500
3000
2500 2000
1500
1000
-1
wavenumbers/cm
Fig. 5 The in situ DRIFTS spectrum of the synthesis of the morpholine(III), methylmorpholine(II) and
ethylmorpholine(II) from DEG(IV), alcohol and ammonia varies with the reaction time at 220 °C
amination reaction generated enamine, thus reducing the intensity of absorption
band of the imine. It can be found in the above information that the spectrum from
the reaction between DEG(IV) and methanol was similar to that from the reaction
between DEG(IV) and methylamine. In addition, if the synthesis of methylmor-
pholine(II) is along the path of the reaction between morpholine(III) and methanol,
then morpholine(III) should exist as an intermediate. However, almost no
morpholine(III) was detected in the reaction mixtures which were analyzed by
gas chromatography. This fact proved that the synthesis of methylmorpholine(II)
proceeds along the path of the reaction between DEG(IV) and methylamine. Taking
into account that the spectrum of the reaction between DEG(IV) and methanol and
123

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C. Luo et al.
the spectrum of the reaction between DEG(IV) and ethanol were similar, the
proposed route can be confirmed.
Conclusions
Compared with reported procedure, Khan [17] synthesized N-butylmorpholine from
morpholine and 1-chlorobutane (morpholine:choromethane = 1:1.1, mole ratio) at
room temperature for 48 h, with a yield of 81 %. Although this method has high
yield, low cost and a simple process, the generated hydrogen chloride salified with
morpholine which reduced the utility of morpholine. In addition, the hydrogen
chloride seriously corroded the reactor. Zhang [18] synthesized N- methylmorpho-
line from morpholine, paraformaldehyde and methanoic acid at 115 °C for 20 min,
with a yield of 95 %. The method has high yield, short reaction time and a simple
process, but the raw materials were expensive and largely consumed. In addition,
the reaction was of low atom economy and had high production costs. In this paper,
the synthesis of N-alkylmorpholines from DEG(IV), methanol and ammonia in gas–
solid phase was investigated in a fixed-bed reactor over CuO–NiO/c-Al2O3 at the
temperature of 220–225 °C, hydrogen pressure of 0.9–1.0 MPa and LHSV of
0.25 h-1, with a yield of 86.4 %. Compared to the above methods, this method is of
high selectivity, with less pollution, and it is easy to achieve continuous production.
The mechanism of the heterogeneous catalytic reaction of DEG and amination to
N-alkylmorpholines was investigated via in situ DRIFTS. CuO–NiO/c-Al2O3 was
selected as catalyst, and Al2O3 was chosen as a suitable carrier. The total gas flow
was optimized to 15*25 mL min-1, in which H2 flow was 15 mL min-1, and the
NH3 flow was 5 mL min-1. The mechanism of synthesis of N-alkylmorpholines
was proposed and proved that it proceeded along the path of the reaction between
DEG and alkylamine.
Acknowledgments We gratefully acknowledge the generous financial support by a grant from the
National Natural Science Foundation of China (No. 21006087), the Natural Science Foundation of the
Zhejiang Province (No. Y4100147), Zhejiang low carbon fatty amine Engineering Technology Research
Centre (2012E10033) and the Fundamental Research Funds for the Central Universities (2011QNA4018).
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