Highly selective phosgene-free carbamoylation of aniline by dimethyl carbonate under continuous-flow conditions

Article abstract of DOI:10.1021/op4000048

Over the last 20 years organic carbamates have found numerous applications in pesticides, fungicides, herbicides, dyes, pharmaceuticals, cosmetics, and as protecting groups and intermediates for polyurethane synthesis. Recently, in order to avoid phosgene-based synthesis of carbamates, many environmentally benign and alternative pathways have been investigated. However, few examples of carbamoylation of aniline in continuous-flow apparatus have been reported. In this work, we report a high-yielding, dimethyl carbonate (DMC)-mediated carbamoylation of aniline in a fixed-bed continuously fed reactor employing basic zinc carbonate as catalyst. Several variables of the system have been investigated (i.e. molar ratio of reagents, flow rate, and reaction temperature) to optimize the operating conditions of the system.

Full text of DOI:10.1021/op4000048

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Full Paper
Highly selective phosgene-free carbamoylation of aniline
by dimethyl carbonate under continuous-flow conditions
Sandra Grego, Fabio Aricò, and Pietro Tundo
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op4000048 • Publication Date (Web): 13 Mar 2013
Downloaded from http://pubs.acs.org on March 18, 2013
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Highly selective phosgeneꢀfree carbamoylation of
aniline by dimethyl carbonate under continuousꢀflow
conditions
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a
a
a,*
Sandra Grego, Fabio Aricò and Pietro Tundo
a
Department of Environmental Sciences, Informatics and Statistics, Ca’ Foscari University of
Venice, Dorsoduro 2137, 30123 Venezia. Tel: (+39) 041 234 8642, Fax (+39) 041 234 8620.
KEYWORDS: Methyl phenylcarbamate, Dimethyl carbonate, ContinuousꢀFlow, Green
Chemistry, Catalysis.
ABSTRACT Over the last twenty years organic carbamates have found numerous applications
as pesticides, fungicides, herbicides, dyes, pharmaceuticals, cosmetics, as protecting groups and
intermediates for polyurethane synthesis. Recently, in order to avoid phosgene based synthesis of
carbamates, many environmentally benign and alternative pathways have been investigated.
However, few examples of carbamoylation of aniline in continuousꢀflow apparatus have been
reported. In this work, we report a high yielding, dimethyl carbonate (DMC) mediated
carbamoylation of aniline in a fixed bed continuously fed reactor employing basic zinc carbonate
as catalyst. Several variables of the system have been investigated, i.e., reagents molar ratio, flow
rate and reaction temperature so to optimize the operating conditions of the system.
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. Introduction
Organic carbamates are industrial relevant compounds which over the last twenty years have
found numerous applications as pesticides, fungicides, herbicides, dyes, pharmaceuticals,
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cosmetics and as protecting groups. Carbamates can also be readily converted into isocyanates
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for polyurethane synthesis via thermo decomposition.
Industrially, these compounds are synthesised predominantly via phosgene routes, i.e. by
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reacting the parent amine with chloroformate. Due to the toxicity of this process, in recent years
many environmentally benign and alternative pathways have been investigated. Some examples
of this being: oxidative carbonylation of amines, reductive carbonylation of aromatic nitro
compounds, methoxycarbonylation via carbonate chemistry and reaction of urea with
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symmetrical carbonates. The latter synthesis, although very efficient, can only be used when
the two components (urea and carbonate) are either both aliphatic or aromatic, limiting the
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possible number of accessible products.
Among the above mentioned reactions, the carbamoylation of aniline via dimethyl carbonate
(
DMC) chemistry is probably the most promising phosgeneꢀfree route to carbamates.
In fact, short chain dialkyl carbonates (DACs) and in particular DMC are renowned for
possessing properties of low toxicity and high biodegradability, which make them true green
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solvents and reagents. Furthermore, DMC has been used as an efficient ecoꢀsustainable
substitute of the most common methoxycarbonylating and methylating agents such as phosgene,
methyl halides or dimethylsulfate showing high selectivity with different monodentate and
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bidentate nucleophiles.
Over the last ten years, reactions between amines and symmetrical DACs have been
investigated resulting in the highly selective synthesis of monoalkyl, dialkyl derivatives and in
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some cases of the related carbamate. However, in most cases, the synthesis of carbamates result
in poor atom economy due to the presence of the corresponding alcohol byꢀproduct.
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Recently several examples of carbamoylation of aniline, 4,4'ꢀmethylenedibenzenamine (for
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the synthesis of methylene diphenyl diisocyanate, MDI) and 2,4ꢀdiaminotoluene (for the
synthesis of toluene diisocyanate TDI) have been reported by DMC chemistry in the presence of
either homogeneous or supported catalysts. An example is the efficient carbamoylation of 2,4ꢀ
diaminotoluene (DAT) by goldꢀcatalyzed phosgeneꢀfree synthesis. This approach is particularly
interesting as it can be extended to a oneꢀpot process which starting from 2,4ꢀdinitrotoluene leads
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directly to the polyurethane precursor TDI. Several syntheses of carbamates involving the use
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of DACs have also been extensively investigated.
Furthermore, our group has recently reported a comprehensive study on the synthesis of
methyl phenylcarbamate from aniline and DMC in the presence of homogeneous, supported
heterogeneous and heterogeneous catalysts in batch conditions. A selection of homogeneous
catalysts have been studied and their reactivity compared to that of zinc acetate, a catalyst
extensively used for this reaction. The best homogeneous catalysts were then supported on silica
or alumina and the resulting heterogeneous supported catalysts investigated for the
carbamoylation of aniline. Several heterogeneous catalysts have also been investigated. Among
them, basic zinc carbonate showed to be the best catalyst giving almost quantitative conversion
and selectivity for the methyl phenylcarbamate. Zinc carbonate also proved to be recyclable,
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once recovered from the reaction mixture and calcinated.
It is noteworthy that most of the above mentioned reactions have been carried out in batch
conditions. Few examples of carbamoylation in a continuousꢀflow apparatus have been reported,
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i.e., a semi continuous process for the synthesis of methyl carbamate from urea and methanol
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and a gasꢀsolid oxidative carbonylation reaction of aniline in a semibatched fixedꢀbed reactor.
The latter process employs a NaIꢀPd/C catalyst and the synthesis proceeds in only two hours
with 80% of aniline conversion and 74% carbamate yield.
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Recently an example of high yielding carbamoylation of aromatic anilines employing a
tetranuclear cluster Zn O(OAc) as catalyst has been reported. However, all the reactions have
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mentioned.
Herein we report a high yielding DMC mediated carbamoylation of aniline in a fixed bed
continuously fed reactor. Basic zinc carbonate was selected as catalyst since it was found to be
the most efficient during our batch trials. Several variables have been investigated, i.e., molar
ratio of the reagents, flow rate, reaction temperature, volume of the reactor and catalysis stability
so to optimize the operating conditions of the system.
COOCH3
NH2
HN
O
Cat.
+
+ CH OH
3
MeO
OMe
Scheme 1. Carbamoylation of aniline
2. Results and Discussion
Variation of aniline/DMC ratio
In a first set of experiments the influence of the aniline/DMC molar ratio on the selectivity of
the carbamoylation reaction was investigated. In Table 1 are summarized the conversion and
selectivity of the experiments conducted. The amount of carbamate and urea produced by the
system has been calculated so to compare the grams of products synthesised in the time unit.
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Table 1. Variation of the aniline/DMC ratio in the reaction of aniline with DMC under
continuousꢀflow conditions. Flow rate was 0.05 mL/min.
a
a
#
Aniline/DMC Temp. Conv.
Selectivity (%)
Production rate
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Mol ratio
1/20
°C
%
Carb.
96
Carb. + Urea g/h (Carb + Urea)
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4
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200
99
96
96
94
93
90
0.24
0.45
0.63
0.75
0.98
1/10
1/7
1/5
1/3
200
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200
200
97
96
92
90
95
93
91
88
a
1
Selectivity and production rated have been calculated by HPLC and H NMR analysis
In the first trial the continuously fed reactor (4.15 mL volume), charged with zinc carbonate
catalyst, was heated at 200 °C and the reagents flow rate was set to 0.05 mL/min. A mixture of
aniline/DMC in 1/20 molar ratio was fed into the system. HPLC and NMR analysis of the
resulting mixture indicated a conversion of 99% and a selectivity of 96% (entry1, Table 1).
Decreasing the aniline/DMC molar ratio from 1/20 to 1/10 (entries 1 and 2 respectively, Table 1)
didn’t seem to effect the conversion or the selectivity of the reaction that, in any case, remained
almost quantitative. When the molar ratio was further diminished (entries 3ꢀ5, Table 1) both
conversion and selectivity slightly decreased although they consistently remained above 90%
even when an aniline/DMC molar ratio of 1/3 was used.
In all the experiments carried out, diphenyl urea was the main byꢀproduct formed. This
compound can be easily converted into the methyl phenylcarbamate by transesterification
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reaction with methanol or DMC, so its selectivity has been considered in the calculation of the
continuously fed reactor production rate.
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Considering the economical aspect of an eventual industrial process i.e. lowest amount of
reagents possible and best conversion and selectivity, the results achieved with an aniline/DMC
molar ratio of 1/10 (entry 2, Table 1) represents the most convenient reaction conditions.
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Variation of flow rate
A set of trials was then conducted using the best aniline/DMC molar ratio found (1/10) at 200
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C and selecting different flow rates of the reagents (entries 1ꢀ4, Table 2).
It is evident that increasing the flow rate from 0.03 mL/min to 0.10 mL/min did not result in
any significant difference of conversion and/or selectivity of the methyl phenylcarbamate that
forms in almost quantitative yield. The best results were achieved at 0.10 mL/min flow rate with
98% conversion of the substrate and 97% selectivity of the carbamate.
On the other hand, when the flow rate of the aniline/DMC mixture was further increased to
0.15 mL/min the conversion started to decrease (89%) as the residence time on the catalytic bed
was too short to allow full conversion (entry 4, Table 2).
Table 2. Variation of flow rate in the reaction of aniline with DMC under continuousꢀflow
conditions. Flow rate was 0.05 mL/min.
#
Flow rate
mL/min
0.03
Temp. Conv.
Selectivity (%)
Production rate
°C
%
Carb.
93
Carb. + Urea g/h (Carb. + Urea)
1
2
3
4
200
98
94
95
98
98
0.27
0.45
0.93
1.27
0.05
0.10
0.15
200
200
200
98
98
89
94
97
96
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In consideration of the experiments carried out, the optimal flow rate of the system for the
carbamoylation of aniline at 200 °C (aniline/DMC ratio 1/10) is 0.10 ml/min (entry 3, Table 2).
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Variation of temperature
The effect of temperature on the carbamoylation of aniline in the fixed bed continuousꢀflow
reactor was then investigated.
Table 3. Variation of temperature in the reaction of aniline with DMC under continuousꢀflow
conditions. Flow rate 0.05 mL/min.
#
Aniline/DMC Temp. Conv.
Selectivity (%)
Production rate
Mol ratio
1/20
°C
%
Carb.
99
Carb. + Urea g/h (Carb. + Urea)
1
2
3
4
5
6
7
8
9
160
94
99
95
96
95
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95
95
98
97
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0.24
0.24
0.29
0.43
0.45
0.83
0.93
1/20
1/20
1/10
1/10
1/10
1/10
1/10
1/10
180
200
160
180
200
180
200
210
99
99
63
95
98
89
98
97
95
96
92
92
94
94
97
96
a
a
b
b,c
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0.91
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b
c
Result from Table 1 , reported here for comparison; Flow of 0.10 mL/min; Result from Table 2,
reported here for comparison
Three sets of experiments were considered. In a first set of trials a solution of aniline/DMC in a
1
/20 molar ratio was pumped at 0.05 mL/min flow rate through the reactor charged with the zinc
carbonate at different temperatures, i.e., 160ꢀ200 °C (entries 1ꢀ3, Table 3). In all cases the
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conversion ranged from almost quantitative ( ≥ 94%) to quantitative for the reaction at 200 °C
(entry 3, Table 3).
In a second set of experiments an aniline/DMC molar ratio of 1/10 (entries 4ꢀ6, Table 3) was
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employed and the temperature varied from 160 to 200 °C. In this case the best results in terms of
conversion and selectivity were obtained when the reaction was performed at 200 °C (entry 6,
Table 3). In fact, when the reactor temperature was set at 160 °C it resulted in an evident lower
conversion (63%) although the selectivity remain almost unaltered (entry 4, Table 3).
Finally a faster flow rate of the reagents was utilised at different temperatures i.e. 0.10 mL/min
at 180ꢀ200 °C (entries 7ꢀ8, Table 3). Analysis of the product mixture showed that the best result
was achieved when the reaction was performed at 200 °C i.e. 98% conversion and 97%
selectivity (entry 8, Table 3). Operating at higher temperature (210 °C) did not improve the
outcome of the reaction (entry 9, Table 3).
This set of experiments confirm the result already reported in Table 2 (entry 3), in fact the best
results were achieved when the reaction was performed using an aniline/DMC ratio of 1/10 at
200 °C and a flow rate of 0.10 mL/min (entry 8, Table 3).
Catalyst performance versus time
The efficiency of the catalyst over time (180 hours) was considered with the results highlighted
in Figure 1. In the experiment an aniline/DMC solution (1/10 molar ratio) was injected at 0.05
mL/min into the reactor set at 200 °C.
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Figure 1. Conversion and selectivity percentage versus time in the reaction of aniline with DMC
under continuousꢀflow conditions.
Samples were collected over time showing that conversion and selectivity were in any case
above 90 % for the entire duration of the trial. It is noteworthy that the performance of the
catalyst appeared to be slightly improved after 60ꢀ70 hours. Furthermore, when the experiment
was stopped (at 48h, 103h and 149 h, Figure 1) and restarted the following day, the activity of
the catalyst remained unaltered as the carbamoylation of aniline proceeded in high conversion
and selectivity toward the methyl phenylcarbamate.
During the reaction time ca 60 g of aniline were fed in the reactor and converted in the related
carbamate using an overall amount of catalyst of 2.48 g of catalyst, which was still active at the
end of the experiment.
Furthermore the amount of zinc carbonate present in the product mixture was measured using
atomic absorption spectroscopy analysis. Results indicated that only 0.8 mg Zn/L were present in
the solution demonstrating that the catalyst is stable in the reaction bed and that it is suitable for
use in a long term continuous process.
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Variation of reactor volume.
The effect of the reactor volume was also evaluated. The continuously fed reactor, employed
for all the above reported trials had a volume of 4.15 mL. For this experiment, a bigger reactor
with a capacity of 10.73 mL was built up in order to evaluate the possibility to scale up the
process. In this new reactor, both the amount of the catalyst and the flow rate were increased (ca
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.5 times) in order to maintain the same residence time of the smaller reactor (ca 35 min). As a
results both conversion and selectivity were coherent with the results so far achieved (entries 1ꢀ
2
,Table 4).
This experiment proves that the reaction can be easily scaledꢀup using bigger reactors without
effecting the conversion and selectivity of the carbamoylation of the aniline.
Table 4. Variation of volume of the fixed bed continuousꢀflow reactor used for carbamoylation
of aniline. Aniline/DMC ratio 1/10, temperature 200 °C.
#
Reactor Vol. Flow.
Conv.
Selectivity (%)
Production rate
mL
mL/min %
Carb.
97
Carb. + Urea g/h (Carb. + Urea)
a
1
2
4.15
0.10
0.25
98
97
98
97
0.93
2.23
10.73
96
a
Result from Table 2 (entry 3) , reported here for comparison.
3. Conclusion
The direct carbamoylation of aniline in a fixed bed continuously fed reactor charged with basic
zinc carbonate reactor has been reported.
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Results collected demonstrated that, in this continuousꢀflow system, zinc carbonate performs
efficiently for the DMC mediated synthesis of methyl phenylcarbamate leading to an almost
quantitative conversion of the reagent and high selectivity of the carbamate.
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Several reaction conditions were investigated i.e. aniline/DMC molar ratio, flow rate,
temperature, reactor volume and efficiency of the catalyst vs time. The optimum conditions
found for a reactor with a capacity of 4.15 mL were an aniline/DMC ratio of 1/10, temperature
of 200 °C and a flow rate of 0.10 mL/min resulting in 98% conversion and 97% selectivity.
The carbamoylation reaction was also conducted on a larger scale employing a reactor with
double the capacity (10.73 mL), achieving similar results in terms of conversion and selectivity.
Finally, the stability of the catalyst was also take into account performing the reaction at 200°C
for a total of 180 hours. The catalyst gave efficient conversion and selectivity throughout without
showing any loss of activity. Furthermore, negligible leaching of the zinc carbonate was
observed.
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. Experimental Section
All reactions were performed employing DMC purchased by Sigma Aldrich dried on 4Å
molecular sieves.
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Figure 2. Fixed bed continuousꢀflow reactor used for the experiments
Aniline and basic zinc carbonate was purchased by Sigma Aldrich and used without any
further purification. Aniline, methyl phenylcarbamate and diphenylurea concentrations were
analyzed by HPLCꢀUV using nitrobenzene as internal standard. The HPLC response factor was
calculated using a standard mixture of methyl phenylcarbamate (87.3% mol) and
Nꢀmethyl
1
aniline (12.7% mol). The standard mixture was prepared, quantified by HꢀNMR and HPLC
analysis.
The fixed bed continuousꢀflow reactor, used for the reactions, consisted of a stainless steel tube
(
4.15 mL capacity, 4.6 mm. id, length 250 mm) thermostated with a coiled heating band (Figure
2). Zinc carbonate was charged into the reactor and packed manually. The aniline/DMC solution
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was fed by a Jasco 880 PU HPLC pump. Products formed, were cooled by a condenser and
collected via a proportional relief valve, set at p = 15 bar.
The production rate of the system have been calculated as follows:
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Aniline (eq./h) = [% aniline * flow rate (ml/min) * 60 * density of the mixture]/MW aniline
Eq. mol. (carb+urea) (eq./h) = Aniline (eq./h) * % Conversion * % Selectivity
Grams (carb+urea/h) = Eq. mol. (carb+urea) * MW
AUTHOR INFORMATION
Corresponding Author
*
Prof. Pietro Tundo, Department of Environmental Science, Informatics and Statistics, Ca’
Foscari University, Dorsoduro 2137, 30123 Venezia.
Tel: (+39) 041 234 8642, Fax (+39) 041 234 8620.
Email: tundop@unive.it
ACKNOWLEDGMENT
We want to thank Renato Paludetto for his contribution and Dow Italia S.r.l. Porto Marghera for
support and funding this work.
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Graphical Abstract
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