Zinc monoglycerolate as a catalyst for the conversion of 1,3- and higher diols to diurethanes

Article abstract of DOI:10.1039/c5ra05032d

A green methodology exploring the scope of diurethane synthesis from diols and urea in the presence of a homogeneous catalyst is described. Past reactions of diurethanes have relied heavily on environmentally corrosive reagents such as phosgene. Prior to this work, we have utilized metal glycerolates as homogeneous catalysts in the glycerolysis of urea. Here we explore the synthetic scope of this system with a variety of diols. The conversion to diurethanes is proposed to proceed via an intermediate zinc bound isocyanate ligand, which rearranges to form the terminal urethane in the case of 1,3- and higher diols in good selectivity and yields. With butane 1,2,4-triol the selectivity is exclusively for the 5-membered carbonate, suggesting that the proximity of the second hydroxyl group is critical in forming the ring.

Full text of DOI:10.1039/c5ra05032d

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Zinc monoglycerolate as a catalyst for the
conversion of 1,3- and higher diols to diurethanes†
Cite this: RSC Adv., 2015, 5, 47809
Sanjitha Kulasegaram,a Uzma Shaheen,a Terence W. Turney,ab Will P. Gatesc
a
*
and Antonio F. Patti
A green methodology exploring the scope of diurethane synthesis from diols and urea in the presence of a
homogeneous catalyst is described. Past reactions of diurethanes have relied heavily on environmentally
corrosive reagents such as phosgene. Prior to this work, we have utilized metal glycerolates as
homogeneous catalysts in the glycerolysis of urea. Here we explore the synthetic scope of this system
with a variety of diols. The conversion to diurethanes is proposed to proceed via an intermediate zinc
bound isocyanate ligand, which rearranges to form the terminal urethane in the case of 1,3- and higher
diols in good selectivity and yields. With butane 1,2,4-triol the selectivity is exclusively for the
5-membered carbonate, suggesting that the proximity of the second hydroxyl group is critical in forming
the ring.
Received 22nd March 2015
Accepted 19th May 2015
DOI: 10.1039/c5ra05032d
www.rsc.org/advances
anemia and is hepatotoxic.8 Other popular 1,3-dicarbamate
derivatives sold as anxiolytic drugs today are meprobamate and
mebutamate, but these too possess unfavourable side effects.9
Introduction
Sustainable development is vital in today's over-polluted world.
Hence the need for green chemical methods outweighs tradi-
tional reaction pathways. There is a drive to develop cheap eco-
friendly solvent-free processes to synthesise ne chemicals.1 In
reactions that are initiated by a catalyst the ideal is to sustain
the atom economy, which will in turn lead to ease of isolation of
the product and cost effectiveness of the process. Our previous
work2 utilized glycerol as a cheaply available starting material in
the glycerolysis of urea (also a low cost and readily available
reactant) to form glycerol carbonate in the presence of a metal
glycerolate catalyst. There are a number of reports on the
reaction of glycerol with urea using various zinc containing
catalysts.3–5
Here we report the extension of our previous work2 to other
1,2 diols as well as the preferential formation of diurethanes
from 1,3- and higher diols via a green chemical process. There
has been a growing market for diurethane derivatives in
medicinal use since the 1950's. Past synthesis of diols to diu-
rethanes have looked at the anticonvulsant properties of
1,3-propanediol derivatives.6 This was followed in the 1960's by
an extensive review of a series of carbamates that were tested in
anticonvulsant animal models.7 One of the more successful
candidates to emerge in the 1990's as an antiepileptic was fel-
bamate, a 1,3-dicarbamate, however it does cause aplastic
Hence the arena is open to explore new carbamate candidates
that are potential anti-epileptics and CNS drugs via a synthetic
strategy that does not involve toxic reagents. This need gave
purpose to our current methodology that yields dicarbamates
from diols in the absence of an external isocyanate reagent.
In moving to 1,3- and higher terminal diols, we observed that
cyclization to larger ring carbonates did not occur and instead
the process stopped once the diurethane was formed. Previous
syntheses of diurethanes have proceeded via reacting diols with
phosgene to give the chlorocarbonate which then reacts with
ammonia to form the urethane (Scheme 1).10
Analogous to the O-bonded diurethanes which are derived
from diols, the N-bonded diurethanes are accessed from
diamines and the relevant carbonate. Zinc based catalysts are
known to effect this transformation either via a heterogeneous
or homogeneous mechanism (Scheme 2).11 These monomers
undergo subsequent polymerization reactions, unlike their
O-bonded counterparts.
An early approach in the 1950's utilized sub-atmospheric
pressures, where a series of 1–3, 1–4 and 1–5 diols were reac-
ted with alkyl urethanes at 140–180 ꢀC at pressures of
20–300 mbar.12,13 The catalyst employed was aluminium
alkoxide and the mixture was kept vigorously boiling in the
absence of extraneous solvent. The resultant alcohol from this
reaction was continuously removed, in order to enhance the
process (Scheme 3).
aSchool of Chemistry Monash University, Victoria 3800, Australia. E-mail: tony.patti@
monash.edu
bDepartment of Materials Engineering, Monash University, Victoria 3800, Australia
cDepartment of Civil Engineering, Monash University, Victoria 3800, Australia
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra05032d
Instead of utilising urethanes, we directly employed urea
with zinc monoglycerolate as a catalyst in a solvent free
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Scheme 1
Scheme 2
Scheme 3
Scheme 4
environment, yielding good conversions and selectivities pressure and 400 mbar, respectively. The two reactions were
(Scheme 4).
monitored over 24 h compared to the usual 7 h. In the case of
ethylene glycol the nal yield of the cyclic carbonate was low, in
spite of the conversion being quite high. We attribute this to the
two-step reaction in forming the cyclic carbonate, where the
rst step proceeds with ease to form the terminal urethane, but
once formed, the cyclization to form the carbonate requires a
catalyst, as well as heat and reduced pressure, to eliminate
ammonia. Details of the mechanism for this reaction have been
described by Turney et al.2 In a previous study, it was shown that
the polymeric glycerolate complexes of Zn or Co form a homo-
geneous catalyst, containing a coordinated isocyanate ligand.
This complex subsequently reacts with a hydroxyl group of the
diol to give a zinc coordinated urethane intermediate. The
proximity of a second hydroxyl group in the 2-position favours
cyclic carbonate formation, as was previously shown.2 However
Results and discussion
We have shown that reacting glycerol with urea in the presence
of zinc monoglycerolate at a temperature of 140 ꢀC and a
pressure of 40 mbar gives glycerol carbonate in high conversion
and yield. When the scope of this methodology was explored
with a series of diols and polyols we observed that with 1,2-diols,
the preferred selectivity was to form the cyclic carbonate with
the terminal urethane intermediate as a side product.2 With the
polyols listed in Table 1, it was essential to apply reduced
pressure to the system, thereby removing ammonia, in order to
promote all the conversions.
In the case of ethylene glycol and propylene glycol, as these
are more volatile, the reactions were carried out at atmospheric
Table 1 Zinc monoglycerolate catalyzed reactions of 1,2-diols with ureaa,e
Substrate
Product
Time/h
Conversion (%)
Selectivity (%)
Glycerol
Glycerol carbonate14
7
24
24
7
7
7
98
71
99
73
87
70
58
85
43c
80
91
86
67
76
Ethane-1,2 diolb
Ethylene carbonate15
Propane-1,2-diold
Butane-1,2,4-triol
cis-Cyclohexane-1,2-diol
trans-Cyclohexane-1,2-diol
1,2-Dihydroxy benzene
Propylene carbonate15
4-(2-Hydroxyethyl)-1,3-dioxolan-2-one16
Hexahydrobenzo[d][1,3]dioxol-2-one17
Cyclohexane-1,2-diyl dicarbamate
2-Hydroxyphenyl carbamate18
7
a
Unless otherwise stated all reactions were performed at 140 ꢀC/40 mbar, with 1.5 mole equivalents of urea to glycerol and 5% wt zinc
b
c
d
monoglycerolate to alcohol. Performed at standard pressure. Selectivity for terminal mono-carbamate intermediate was 37%. Pressure was
400 mbar. e Analytical data for these compounds is provided in the ESI.
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Table 2 Zinc monoglycerolate catalyzed reactions of 1,3- and higher diols with ureaa,e
Substrate
Product
Conversion (%)
Selectivity (%)
Yield (%)
1,3-Propane diolb
1,4-Butane diol
1,6-Hexane diol
Propane-1,3-diyl dicarbamate19
75
71
84
82
66
86
68
74
86
75
76
94
87
86
84
80
93
93
56
54
79
71
57
72
54
69
80
Butane-1,4-diyl dicarbamate19
Hexane-1,6-diyl dicarbamate19
1,8-Octane diol
Octane-1,8-diyl dicarbamate19
1,10-Decane diol
Diethylene glycol
Triethylene glycol
Pentaerythritolc
Decane-1,10-diyl dicarbamate19
Oxybis(ethane-2,1-diyl) dicarbamate20
(Ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) dicarbamate21
Tetra carbamate of pentaerythritol22
2-(Hydroxymethyl)phenyl carbamate
2-(Hydroxymethyl) phenold
a
Typical reaction conditions were 5% wt zinc monoglycerolate to substrate with 2 mole equivalents of urea heated to 140 ꢀC under a reduced
b
c
d
pressure of 40 mbar over 7 h. Pressure used was 400 mbar over 24 h. Used a 5 mole excess of urea. Used 1.5 mole equivalents of urea.
e
Analytical data for these compounds is provided in the ESI.
in diols or other alcohol systems where the hydroxyl group is not
When we proceeded to look at higher diols (>1, 3-), with 2
in a 1,2 relationship, linear urethane products are favoured. equivalents of urea and 5% wt catalyst at a temperature of
This requires further reaction of the free hydroxyl of the mon- 140 ꢀC and a pressure of 40 mbar, we observed the predominant
ourethane with the catalyst, to form the diurethane.
formation of diurethanes rather than cyclic carbonates
With ethylene glycol we were unable to exert reduced pres- (Table 2).
sure on the system and maintain the temperature at 140 ꢀC
Under these solvent free conditions, once the urea and diol
without also losing the starting material and products (despite are in a liquid phase and the catalyst is homogeneous, product
the use of a water condenser), which resulted in poorer selec- formation begins where the long chain diurethanes deposit as a
tivity. In the reaction of 1,2-propylene glycol, which was less solid in the reaction mixture even at elevated temperatures. In
volatile than ethylene glycol, a reduced pressure of 400 mbar general this methodology with terminal diols is robust when
was applied over 24 h, in order to maximize conversion and zinc monoglycerolate is used as a catalyst, consistently yielding
selectivity. The higher selectivity for the cyclic carbonate in this the diurethane in good yield. It was also possible to recover and
instance is a direct effect of the applied reduced pressure, which reuse the catalyst, in the same way as described in our previous
promotes the cyclization with the removal of ammonia. In the work.2 In progressing to a C-10 chain there is a slight drop in
case of the cis and trans 1,2-diols of cyclohexane, the expected conversion which affects the yield. Here the long alkyl chains
carbonate was obtained with the cis-isomer. The trans-isomer of may serve as deterrents towards the approaching metal bound-
the mono-urethane intermediate however is stereochemically isocyanate and hinder the conversion. With polyethylene glycol
too rigid to successfully undergo an intra-molecular nucleo- derivatives the transformation was similar to long chain
philic substitution, instead the diurethane is formed in pref- hydrocarbon moieties.
erence (Table 1, 67% selectivity) along with minor amounts of
Reaction of thiourea with 1,6-hexanediol under our opti-
the mono-urethane (9%) and cyclic carbonate (6%). On applying mized conditions with ZMG did not yield the desired cyclic
this methodology to an aryl 1,2-diol such as catechol, we carbonate even though there was IR evidence for a thio-
obtained the mono-urethane intermediate with poor conversion isocyanate species (2050 cmÀ1) during the course of the reac-
and yield; none of the cyclized product was observed over 7 h. tion. The unreacted diol was recovered quantitatively. The
This mixture blackens within 1 h of heating under our standard reaction of this diol with 1.5 mole equivalents of biuret resulted
conditions. Similarly with 2-(hydroxymethyl) phenol, the major in 75% conversion, where the exclusive product was the mono-
product was the mono-urethane with preference for carba- carbamate. The reaction of 1,6-hexanediol with 2 mole equiva-
moylation taking place on the aryl rather than the benzylic lents of tetramethyl urea under optimal conditions did not yield
oxygen (Table 2).
any carbamate. When 1,6-hexanediol was reacted with 2 mole
Table 3 Zinc monoglycerolate catalyzed reactions of 1,6-hexanediol with urea derivativesa
Urea derivative
Product
Conversion (%)
Selectivity (%)
Yield (%)
Thiourea
n/a
0
75
65
0
0
100
88
0
75
57
0
Biuret
Mono-carbamate23
Mono-N,N-dimethylcarbamate
n/a
N,N-Dimethyl ureab
Tetramethyl urea
0
a
Typical reaction conditions were 5% wt zinc monoglycerolate to substrate with 2 mole equivalents of the urea derivative heated to 140 ꢀC under a
b
reduced pressure of 40 mbar over 7 h. 400 mbar pressure was used.
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equivalents of N,N dimethylurea, 65% conversion was achieved
with the formation of the monocarbamate. A minor byproduct
(<12%) was not fully characterised, however mass spectrometry
evidence suggested it may be the disubstituted N,N dime-
thylcarbamate (Table 3).
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Experimental
The general method to convert diols to either the cyclic
carbonate or the diurethane was as follows: a mixture of diol
(0.066 mol), urea (0.132 mol) and 5% wt zinc monoglycerolate
(0.25 g) with respect to the diol, were heated to 140 ꢀC at a
reduced pressure of 40 mbar in a round bottom ask tted with
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ltered and concentrated to obtain an oil. With solid diu-
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The authors are grateful to Micronisers Pty Ltd for supply of zinc
glycerolate nanoparticles, the Australian Research Council for
nancial support (Grant no.: DP1095129), the Faculty of Science
for providing an international PhD fees scholarship (US) and
wish to thank Mingdeng Luo and Sally Duck from Monash
University for instrumental support.
47812 | RSC Adv., 2015, 5, 47809–47812
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