Simplification of the synthesis of the reversible addition-fragmentation chain transfer agent 2-(2-cyanopropyl)-dithiobenzoate

Article abstract of DOI:10.2298/JSC100628082M

The general literature procedure for the preparation of the reversible addition-fragmentation chain transfer (RAFT) agent 2-(2-cyanopropyl)- dithiobenzoate (CPDB) was modified by omitting the recrystallisation of the intermediate di(thiobenzoyl)disulphide. The yield of the CPDB in the simplified synthesis was increased four times compared to the standard one. The behaviour of the CPDB obtained by the modified procedure and by the standard one in the polymerisation of methyl methacrylate was investigated. The CPDB synthesized by the simplified procedure showed itself to be a good RAFT agent, giving excellent control over the polymerisation of methyl methacrylate and it behaved in the same manner as the CPDB prepared by the literature method. The obtained poly(methyl methacrylate) had a narrow molecular weight distibution (PD = 1.1).

Full text of DOI:10.2298/JSC100628082M

J. Serb. Chem. Soc. 75 (12) 1711–1719 (2010)
UDC 678.744+661.8’078.2:542.913
JSCS–4090
Original scientific paper
Simplification of the synthesis of the reversible
addition–fragmentation chain transfer agent
-(2-cyanopropyl)-dithiobenzoate
2
1
#
2
MILOŠ B. MILOVANOVIĆ , MILENA AVRAMOVIĆ ,
2
2#
LYNNE KATSIKAS * and IVANKA G. POPOVIĆ
1
Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Belgrade and
2
Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Serbia
(Received 30 June 2010)
Abstract: The general literature procedure for the preparation of the reversible
addition–fragmentation chain transfer (RAFT) agent 2-(2-cyanopropyl)-dithio-
benzoate (CPDB) was modified by omitting the recrystallisation of the inter-
mediate di(thiobenzoyl)disulphide. The yield of the CPDB in the simplified
synthesis was increased four times compared to the standard one. The be-
haviour of the CPDB obtained by the modified procedure and by the standard
one in the polymerisation of methyl methacrylate was investigated. The CPDB
synthesized by the simplified procedure showed itself to be a good RAFT
agent, giving excellent control over the polymerisation of methyl methacrylate
and it behaved in the same manner as the CPDB prepared by the literature me-
thod. The obtained poly(methyl methacrylate) had a narrow molecular weight
distibution (PD = 1.1).
Keywords: 2-(2-cyanopropyl)-dithiobenzoate; preparation; reversible addition–
–
fragmentation chain transfer; poly(methyl methacrylate).
INTRODUCTION
In recent years, much effort has been focused on the synthesis of polymers
with controlled molar masses and very narrow molar mass distributions. With the
development of several methods of controlled radical polymerisation, well-de-
fined polymers with complex architectures, including block,1 graft and star
,2
3
4,5
structures, could be prepared. The development of these methods was promoted
by the growing need for truly living radical polymerisation systems that would
offer all the benefits of ionic polymerisations without the serious disadvantages
inherent to such systems. Among them, RAFT (reversible addition–fragmen-
*
Corresponding author. E-mail: Lynne@tmf.bg.ac.rs
Serbian Chemical Society member.
#
doi: 10.2298/JSC100628082M
1
711
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MILOVANOVIĆ et al.
tation chain transfer) polymerisation has proven itself to be the most versatile
one, since it is applicable to a wide range of monomers and can be performed in a
wide variety of solvents over a broad range of experimental conditions. RAFT
polymerisations are now being used successfully by an ever-growing number of
research groups around the world. The key to successful RAFT polymerisations
is the presence of a highly efficient dithioester chain transfer agent. Among nu-
merous RAFT agents, only a few are commercially available (carboxymethyl
dithiobenzoate, for example). Regarding the importance of the synthesis of RAFT
agents of different structures, a large number of procedures for the synthesis of
dithioester compounds have been developed. As the syntheses of these RAFT
agents are usually costly and require multi-step reactions, the loss of polymeri-
sation mediator throughout the RAFT polymerisation process may be an issue
when scaling-up the process. A simple reaction that leads to the full removal of
the thiocarbonyl-thio end group from the polymeric chains and recovery of the
6
chain transfer agent has already been reported. In addition, simplifications of the
syntheses of RAFT agents would promote scaling-up the RAFT polymerisation
processes.
This study focused on the synthesis of 2-(2-cyanopropyl)-dithiobenzoate
(
CPDB) which, together with cumyl dithiobenzoate, is one of the most frequently
employed RAFT agents. CPDB was reported to be an efficient RAFT agent in
7
–10
the polymerisation of a number of monomers.
2-(2-Cyanopropyl)-dithioben-
zoate can be synthesized in two ways. One method is a single-step procedure, by
reaction of Davy reagent or P4S10 with benzoic acid. The obtained CPDB was
used to control in situ the free-radical polymerisation of styrene and alkyl
1
1
(
meth)acrylates. The isolation of pure CPDB demands a multi-step proce-
1
2
dure. One of the steps in this preparation is the synthesis of dithiobenzoic acid.
Dithiobenzoic acid is unstable and should be stored at low temperatures (< –20
C) or used immediately. For this reason, it is usually transferred into di(thio-
1
3
°
benzoyl)disulphide. Di(thiobenzoyl)disulphide is used not only for the synthesis
1
4
of CPDB, but also for the syntheses of many different RAFT agents.
In the present study, the standard procedure for the preparation of CPDB was
modified and simplified by omitting the intermediate step of the recrystallisation
of di(thiobenzoyl)disulphide in order to avoid great loss of material in this step.
The behaviour of the CPDB synthesized by the simplified procedure in the po-
lymerisation of methyl methacrylate was investigated and compared with that of
the CPDB synthesized by the standard method.
EXPERIMENTAL
Methyl methacrylate, MMA, (Fluka) was distilled under reduced pressure after removal
of the inhibitor with a 10 % aqueous NaOH solution. Azobis(isobutyronitrile), AIBN, (Ald-
rich), was purified by recrystallisation from methanol. Benzene, thiophene free, (Fluka) was
distilled before use.
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SIMPLIFIED SYNTHESIS OF 2-(2-CYANOPROPYL)-DITHIOBENZOATE
1713
The RAFT agent, 2-(2-cyanopropyl)-dithiobenzoate (CPDB), was prepared by a standard
method described in the literature.15 To a thoroughly dried, three-necked round-bottomed flask
equipped with a magnetic bar, addition funnel, thermometer and condenser was added ele-
mental sulphur (6.4 g, 0.20 mol), 25 % sodium methoxide solution in methanol (40 g) and
anhydrous methanol (40 g). Benzyl chloride (12.6 g, 0.10 mol) was the added dropwise via an
addition funnel over a period of 90 min at room temperature. The resulting violet-brown so-
lution was then heated and allowed to reflux overnight. After cooling to room temperature, the
mixture was filtered to remove the white solid (sodium chloride) which was formed as a by-
-
product during the reaction. The methanol was removed by rotary evaporation at 40 °C. The
resulting violet-brown solid was then re-dissolved in distilled water (100 ml) and transferred
to a separation funnel. The crude sodium dithiobenzoate solution was washed with diethyl
ether (3×50 ml). A final layer of ether (50 ml) was added to the solution and the two-phase
mixture was then acidified with 32 % aqueous HCl until the aqueous layer lost its characte-
ristic violet-brown colour and the top, ether, layer was deep purple. The ether layer containing
dithiobenzoic acid was extracted. Deionized water (120 ml) and 1.0 M NaOH (240 ml) were
added, and sodium dithiobenzoate was extracted into the aqueous layer. This washing process
was repeated two times more to yield a final solution containing sodium dithiobenzoate (360 ml).
The next step was the synthesis of di(thiobenzoyl)disulphide. Potassium ferricyanide
(
13.17 g, 0.040 mol) was dissolved in deionized water (200 ml). Potassium ferricyanide so-
lution (140 ml) was transferred to a conical flask equipped with a magnetic bar. Potassium fer-
ricyanide solution was added dropwise to the sodium dithiobenzoate via an addition funnel
over a period of 1 h under vigorous stirring. The red precipitate was filtered and washed with
deionized water until the washings become colourless. The solid was dried under vacuum at
room temperature. The product was recrystallized from anhydrous ethanol.
The target compound was prepared in the reaction of di(thiobenzoyl)disulphide with
azobisisobutyronitrile (AIBN). A solution of AIBN (2.90 g, 0.018 mol) and di(thiobenzoyl)di-
sulphide (3.60 g, 0.012 mol) in ethyl acetate (70 ml) was heated at reflux for 18 h. The ethyl
acetate was removed under vacuum. The crude product, CPDB-1, was subjected to column
chromatography on a 25×2.6 cm column filled with silica gel (Woelm mesh size 0.063–0.2
mm, ICN Pharmaceuticals, Germany) as the stationary phase and ethyl acetate: n-hexane
-
1
(
0.2:0.98) as the eluent, at a flow rate of 1.0 mL min .
Due to the large loss of di(thiobenzoyl)disulphide in the recrystallisation step, the syn-
thesis of di(thiobenzoyl)disulphide was repeated but this time it was used in the subsequent re-
action without recrystallisation to yield CPDB-2.
The structure of the CPDB from the both synthesis was confirmed by 13C-NMR spec-
troscopy using a Varian-Gemini-200 (200 MHz) instrument.
In order to determine whether CPDB-2 was equally effective as a RAFT agent as CPDB-1,
methyl methacrylate was polymerised using both RAFT agents.
The polymerisations of methyl methacrylate, MMA, were performed in a three-necked
round-bottomed flask equipped with a magnetic stirring bar, a condenser, a thermometer, an
inlet for nitrogen and a rubber septum for removing samples. The flask was charged with
MMA (30 ml, 0.28 mol), benzene (10 ml, 0.11 mol), AIBN (40 mg, 0.24 mmol) and CPDB
(
104 mg, 0.470 mmol). Nitrogen was bubbled through the reaction mixture for 15 min at room
temperature before starting the polymerisation, while during the polymerisation the nitrogen
stream was directed over the top of the condenser, thus keeping the reaction mixture under a
nitrogen atmosphere. A preheated oil bath was employed to commence the polymerisations.
The polymerisations were performed at 60 °C. Samples were removed from the flask every 2 h
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MILOVANOVIĆ et al.
via a needle and syringe and precipitated into methanol. The polymer samples were repreci-
pitated from chloroform solution into methanol and dried to constant mass at room tempe-
rature under vacuum.
M
n and
M w
The number and weight average molar masses,
, respectively, and the po-
lydispersity index, PD, of the obtained polymers were determined at 30 °C by gel permeation
chromatography, SEC, using a Waters instrument fitted with four analytical columns (Waters
HR 2, HR 3, HR 4 and HR 5E) and a refractive index detector. THF was used as the solvent at
-
1
a flow rate of 1.0 ml min . The obtained chromatograms were analyzed with Waters Breeze
software using a calibration curve of narrow molar mass distribution PMMA standards (PSS
Polymer Standards Service GmbH, Mainz, Germany).
RESULTS AND DISCUSSION
The RAFT agent, CPDB, was prepared in two syntheses which differed in
the recrystallisation of the intermediate di(thiobenzoyl)disulphide. The final pro-
ducts (CPDB1 and CPDB2, with and without recrystallisation, respectively) from
both syntheses were subjected to column chromatography with silica gel as the
stationary phase and ethyl acetate:n-hexane (0.20:0.98) as eluent. The crude pro-
duct made from the di(thiobenzoyl)disulphide recrystallized in ethanol gave se-
ven fractions: green (which did not enter the column), yellow and pink which
stayed on the column, and yellow (eluted first), pink, red and purple which eluted
last. The main purple fraction gave 2-(2-cyanopropyl)-dithiobenzoate as a red-
-
purple liquid after evaporation of the eluent. The yield of the CPDB-1 was ex-
tremely low when the pure substance was obtained (5 % of the theoretical yield).
The crude product from the second synthesis made from the di(thiobenzoyl)-
disulphide without recrystallisation was reddish coloured, but after the column
chromatography it gave the characteristic purple coloured fraction as the main
product. The crude product from this synthesis gave four fractions: yellow and
orange, which stayed on the column, and yellow and the main purple one, which
eluted last. After evaporation of the eluent, the main purple fraction from the se-
cond synthesis gave CPDB-2 as a red-purple liquid.
The fact that more fractions were obtained during the column chromato-
graphy of CPDB-1 than during the chromatography of CPDB-2 indicates that
during recrystallisation not only was di(thiobenzoyl)disulphide inherently lost,
but also that it decomposed. It was observed that a resinous material was formed
during the recrystallisation, which when removed was insoluble in ethanol. This
could be the explanation of the green fraction which did not enter the column.
1
3
The C-NMR spectrum and the numbering of the C atoms of the prepared
CPDB-1 and CPDB-2 are shown in Figs. 1 and 2, respectively, from which it can
be seen that all the expected peaks were present. One additional peak was found
in the spectrum of the CPDB2 (at 23 ppm). This could arise by the recombination
of primary radicals from the decomposition of AIBN, used in the last step of the
1
2
synthesis. It was reported that the highest level of impurity found in CPDB
could be attributed to recombined radicals arising from the decomposition of
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SIMPLIFIED SYNTHESIS OF 2-(2-CYANOPROPYL)-DITHIOBENZOATE
1715
AIBN. This recombination compound was found to be difficult to remove from
the RAFT agent, even after column chromatography, but it is inert to any radical
reaction. The peak of the carbon atoms from the four equivalent CH groups of
3
1
3
such a compound is expected at 23 ppm in a C-NMR spectrum. It is important
to emphasise that the yield of the CPDB in the second synthesis was increased to
2
0 % of theoretical yield, which is four times more compared to the first one.
Fig. 1. 13C-NMR Spectrum of CPDB-1 (inset: structure of CPDB with C atoms numbered).
Fig. 2. 13C-NMR Spectrum of CPDB-2 (inset structure of CPDB with C atoms numbered).
A change in the standard method of preparation of CPDB was previously
1
6
reported in the literature. The alteration concerned of the same step in the
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MILOVANOVIĆ et al.
procedure of CPDB synthesis to which attention was paid in this study. The pu-
rification di(thiobenzoyl)disulphide by the recrystallisation in ethanol was substi-
tuted by column chromatography using ethyl acetate/petroleum ether (1:1) as the
eluent. The yield of CPDB was 50 % of the theoretical one, which is 2.5 times
larger than one obtained in the present study. However, it must be emphasised
that the purification di(thiobenzoyl)disulphide was completely avoided in syn-
thesis procedure employed in this study, which is extremely important for labora-
tory or industrial scale-ups.
Two RAFT polymerisation of methyl methacrylate were performed using
CPDB from the two different syntheses. Samples were taken from the reaction
flask every 2 h. The polymer obtained after the RAFT polymerisation was pink
due to the attachment of CPDB to the chain ends. Two series of PMMA samples
were obtained: PMMA-1 from the polymerisation using the CPDB-1 and PMMA-2
from the polymerisation using the CPDB-2. The number and weight average mo-
lar masses, M n and M w , and the polydispersity index, PD, of the obtained
polymers are given in Table I. The polymerisations mediated by CPDB-1 and
CPDB-2 exhibited very similar kinetics, i.e., the polymerisation rates were very
similar (Fig. 3a).
TABLE I. Number and weight average molar mass and polydispersidity index, PD, of the
PMMA-1 and PMMA-2 samples
PMMA-1
M n / g mol M w / g mol
PMMA-2
M w / g mol
Time, h
-1
-1
-1
-1
PD
M n / g mol
PD
2
4
6
8
16625
19481
25126
30436
37271
18415
21676
27972
34062
41800
1.108
1.112
1.113
1.119
1.122
15161
20872
26071
31958
39412
16674
23001
28901
35648
44310
1.100
1.102
1.109
1.115
1.124
1
0
A comparison of M w of PMMA-1 and PMMA-2 samples as a function of
polymerisation time is shown in Fig. 3b, from which it can be seen that the molar
mass increased with polymerisation time, as is to be expected for RAFT-control-
led polymerisations, and that the rate of increases were very similar. The SEC
chromatograms revealed good control of the CPDB-mediated polymerisations
with narrow molar mass distributions. The comparison of An SEC chromatogram
of a PMMA sample obtained using CPDB-2, is compared with that of the corres-
ponding PMMA sample prepared using CPDB-1, in Fig. 4. As can be seen, the
chromatograms are very similar.
The polydispersities of the PMMA samples from both series (Table I) were
also very similar for the same polymerisation time, indicating that CPDB-1 and
CPDB-2 affected the same polymerisations.
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SIMPLIFIED SYNTHESIS OF 2-(2-CYANOPROPYL)-DITHIOBENZOATE
1717
Fig. 3. a) MMA Conversion vs. polymerisation time in the presence of CPDB-1 and CPDB-2.
b) Weight average molar mass of the PMMA-1 and PMMA-2 samples
vs. polymerisation time.
Fig. 4. SEC Chromatogram of PMMA samp-
les obtained by polymerisation of MMA in
the presence of CPDB-1 and in the presence
of CPDB-2 for 4 h.
As can be seen, the CPDB obtained by the simplified procedure exerted the
same effects in the polymerisation of PMMA as that obtained by the literature
procedure.
CONCLUSIONS
The procedure of CPDB preparation was modified and simplified by omit-
ting the recrystallisation of the intermediate di(thiobenzoyl)disulphide. The yield
of the CPDB in the simplified synthesis was increased by a factor of four com-
paring to the literature method. The CPDB synthesized by the simplified proce-
dure provided very good control of the polymerisation of methyl methacrylate,
yielding PMMA samples with narrow molar mass distibutions, and behaved in
the same manner as the CPDB prepared by the standard literature procedure. The
simplification of the synthesis of CPDB introduced in this study is very important
from the points of view of time, scale-up and amounts of solvents necessary.
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MILOVANOVIĆ et al.
Acknowledgement. This investigation was financed by the Ministry of Science and Tech-
nological Development of the Republic of Serbia, through Project No.142023.
И З В О Д
ПОЈЕДНОСТАВЉЕЊЕ ПОСТУПКА СИНТЕЗЕ RAFT АГЕНСА
2
-(2-ЦИЈАНОПРОПИЛ)-ДИТИОБЕНЗОАТА
1
2
2
2
МИЛОШ Б. МИЛОВАНОВИЋ , МИЛЕНА АВРАМОВИЋ , LYNNE KATSIKAS и ИВАНКА Г. ПОПОВИЋ
1
Institut za hemiju, tehnologiju i metalurgiju, Univerzitet u Beogradu, Beograd
2
Tehnolo{ko-metalur{ki fakultet, Univerzitet u Beogradu, Beograd
Стандардни поступак синтезе 2-(2-цијанопропил)-дитиобензоата (CPDB) агенса из ли-
тературе за RAFT полимеризацију, односно за реверзибилну адиционо-фрагментациону транс-
фер полимеризацију, је модификован изостављањем прекристализације међупроизвода бис-
(тиобензоил)дисулфида. Принос CPDB-а синтетисаног поједностављеним поступком је че-
тири пута већи у односу на принос CPDB-а синтетисаног стандардним поступком. Испитано
је понашање CPDB-а добијеног модификованим и оног добијеног стандардним поступком у
полимеризацији метил метакрилата. CPDB добијен поједностављеним поступком показао се
као добар RAFT агенс који успостављa одличну контролу полимеризације метил метакри-
лата и који се понаша на исти начин као CPDB синтетисан стандардним поступком. Доби-
јени поли(метил метакрилат) има уску ширину расподеле молских маса (PD = 1.1).
(Примљено 30. јуна 2010)
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