Zwitterionic Hydrobromic Acid Carriers for the Synthesis of 2-Bromopropionic Acid from Lactide

Article abstract of DOI:10.1002/cssc.201702369

A convenient and highly efficient way of synthesizing 2-bromopropionic acid (2-BrPA) from lactide is presented. The procedure uses ionic liquids obtained from the addition of HBr to ammonium-based zwitterions as the solvent and bromination agent. The buffered HBr acidity, high polarity, and charge stabilizing character of the ionic liquid (IL) enable the synthesis of 2-BrPA with excellent selectivity. The best results are obtained with an imidazolium-based IL, that is, 1-(4-butanesulfonic acid)-3-methylimidazolium bromide ([MIMBS]Br). The HBr loading and water content of the IL are crucial parameters for the bromination reaction. The formed 2-BrPA product can be selectively isolated by extraction from the IL, and the unconverted substrate remains in the [MIMBS]Br IL for the next run. Successful recycling of the IL over four cycles is demonstrated.

Full text of DOI:10.1002/cssc.201702369

Accepted Article
Title: Zwitterionic HBr carriers for the synthesis of 2-bromopropionic
acid from lactide
Authors: Jakob Albert, Matthias Kehrer, Julian Mehler, Nicola Taccardi,
Jens Nagengast, Julian Kadar, Dimitris Collias, Peter
Dziezok, and Peter Wasserscheid
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.201702369
Link to VoR: http://dx.doi.org/10.1002/cssc.201702369
A Journal of
www.chemsuschem.org

ChemSusChem
10.1002/cssc.201702369
1
Zwitterionic HBr carriers for the synthesis of 2-bromopropionic acid from lactide
a
Matthias Kehrer , Julian Mehler , Nicola Taccardi , Jens Nagengast , Julian Kadar , Dimitris
a
a
a
a
b
Collias, Peter Dziezok, Peter Wasserscheid and Jakob Albert
c
a,d*
*a
a
Institute of Chemical Reaction Engineering, Friedrich-Alexander-University Erlangen-Nürnberg
FAU), Egerlandstrasse 3, 91058, Erlangen, Germany.
(
b
The Procter & Gamble Co, Materials Science Transformative Platform Technologies, Cincinnati,
USA.
c
Procter & Gamble Service GmbH, Sulzbacher Str. 40, 65824 Schwalbach am Taunus, Germany
d
Forschungszentrum Jülich, „Helmholtz-Institut Erlangen-Nürnberg für Erneuerbare Energien“ (IEK
1
1), Egerlandstrasse 3, 91058 Erlangen, Germany
Contact details of the corresponding authors:
Phone: (+49)-(0)9131-85-27420 Fax: (+49)-(0)9131-85-27421; e-mail: peter.wasserscheid@fau.de
Phone: (+49)-(0)9131-85-67417 Fax: (+49)-(0)9131-85-27421; e-mail: jakob.albert@fau.de
Abstract
A convenient and highly efficient way of synthesizing 2-bromopropionic acid (2-BrPA) from lactide is
presented. The procedure uses ionic liquids obtained from the addition of HBr to ammonium-based
zwitterions as solvent and bromination agent. The buffered HBr acidity, high polarity, and charge
stabilizing character of the IL enable 2-BrPA synthesis with excellent selectivity. The best results were
obtained with the imidazolium-based IL 1-(4-butane sulfonic acid)-3-methyl imidazolium bromide
(
[MIMBS]Br). It was found that adjustment of the right HBr loading and the water content of the IL are
crucial parameters for the bromination reaction. The formed 2-BrPA product can be selectively isolated
via extraction from the IL and the unconverted substrate remains in the [MIMBS]Br for the next run.
Successful recycling of the IL over four cycles was demonstrated.
Keywords
2
-bromopropionic acid, lactide, lactic acid, renewable resources, ionic liquids, zwitterions,
bromination, acrylic acid
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
2
Introduction
Bromo-organic compounds are used in diverse chemical reactions like bromination , oxidations ,
[1]
[2]
[
3]
[4]
hydrolysis , substitutions , or catalysis and are therefore involved in the synthesis of complex
[5]
[6]
organic molecules, e.g. in the polymer, pharmaceutical, and agrochemical industries. Due to their
[7]
acidity, reactivity, and distinct biological properties , halogenated carboxylic acids (HCAs) are
[8]
typically used as alkylation and acylation reagents in the chemical industry . 2-Bromopropionic acid,
a bromo-derivative of the above mentioned HCA-group, is used for example in the synthesis of triazole
[9]
derivatives , which have attracted tremendous interest among organic and medical chemists owing to
[10]
their remarkable and wide range of biological activities.
[11]
In addition, a recent publication by Terrade et al.
in this journal as well as contributions from
[12]
Wasserscheid et al. have added a new and highly relevant field to the group of technically interesting
applications of 2-BrPA. These authors have reported a novel method for the production of bio acrylic
acid (bio-AA) from fermentatively produced lactide/lactic acid derivatives. Terrade et al. described a
catalytic cracking of lactide in bromide salts in the presence of a strong acid. This novel process is very
different from the previously described processes to bio-AA from lactic acid (LA) feedstocks, as the
described reaction is a rearrangement of lactide and not a dehydration of LA. Moreover, the reaction is
[11]
performed in the liquid phase at significantly lower temperatures (130 – 175°C) compared to the
[
13]
typical gas-phase process conditions (300 – 500°C).
process for bio-AA production include LA oligomers and LA polymers. The proposed mechanism of
lactide cracking proceeds via brominated LA-species and involves a S 2 / elimination sequence,
forming AA from 2-BrPA, for example. Terrade et al. describe in reference [11] and the related patent
Alternative feedstocks for this liquid-phase
N
[14]
literature AA yields of up to 58% obtained from lactide after 10 h at 175°C (the reaction mixture
included 0.69 mmol lactide, 0.83 eq. of anhydrous methanesulfonic, 5 eq. of tetraphenylphosphonium
bromide, and sulfolane). While this is a remarkable and highly interesting result, the economics of such
an alternative process for bio-AA production from biomass-derived lactide would largely improve if
higher yields are achieved. An obvious approach toward this important goal is to split the reaction
sequence in accordance with the claimed mechanism in two steps, namely a highly selective 2-BrPA
synthesis from LA derivatives and a highly selective dehydrobromination of 2-BrPA to AA. While the
first step requires high HBr concentrations and modest temperatures in order to prevent the
decomposition of the lactide over the carbocation to acetaldehyde and CO, the second step is promoted
by low HBr pressure and basic conditions. From these considerations, we anticipate that there will be a
strong interest in the future in selective 2-BrPA synthesis from lactide in the context of liquid-phase
routes to bio-AA. This could make 2-BrPA a relevant intermediate for acrylic acid production (world-
[15]
wide production ca. 5 Mio tons/year and rising tendency) to enable a bio-based industrial production
[15b, 16]
of the corresponding coatings, plastics, and superabsorbers.
[17]
Currently, 2-BrPA is produced via the Hell-Vollhard-Zelinsky reaction from mainly crude-oil-based
propanoic acid (PA). In this reaction, PA is processed with phosphorous tribromide and elemental
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
3
bromine under elevated temperatures forming considerable amounts of waste by-products. By all
accounts, this process does not include green and sustainable process conditions.
A much more suitable substrate for a sustainable production of 2-BrPA is LA which is commercially
produced by fermentation of sugar. LA is already used as safe and bio-based chemical in the food
industry and for the production of the biodegradable polymer polylactic acid (PLA). The expected drop
in LA cost, resulting from an expected increase in production capacity and improved manufacturing
[18]
technology, will make LA an even more attractive starting material in the future.
Recently, ionic liquids (ILs) have attracted the interest of the scientific community due to their well-
known and interesting properties, offering immense opportunities as, for example, catalysts and novel
[19]
solvents for chemical transformations.
Among the reported ionic liquid-based innovations, new
methods for the halogenation of alcohols and diols appear particularly promising because halide ILs
have been reported as excellent halogenating agents acting at the same time as solvents and vapor
[20]
pressure reducing agents for the applied or formed hydrogen halide acids.
These methods can
overcome some disadvantages of traditional bromination methods for alcohols, including corrosive and
[
21]
toxic halogenation agents, difficult product separation, and low atom economy.
For instance,
[22]
[23]
BASF (chlorination of butane-1,4-diol) and SOLVAY (hydrochlorination of acetylene) already
apply ILs in industrial halogenation processes.
[24]
In 2011, Li et al. reported the use of a zwitterionic HBr-carrier system as bromination medium for
1
,7-heptanediol. In that work, the bromide salt resulting from the addition of HBr to the zwitterion acts
[24]
as catalyst, brominating agent, and solvent. More importantly, the applied HBr is chemically bound
to the zwitterion which greatly reduces HBr vapor pressure and makes the system relatively easy to
handle. In the present contribution, we transfer this methodology to the bromination of functionalized
and much more sensitive bio-based substrates, such as lactic acid and lactide. We show that different
zwitterions can be successfully applied as HBr carriers to enable highly selective bromination of LA to
2
-BrPA. We report on the development of an optimized reaction protocol using the ionic liquid 3-
methyl-1-(4-butane sulfonic acid) imidazolium bromide ([MIMBS]Br) and demonstrate the excellent
recyclability of the IL in this challenging bromination reaction.
Results and Discussion
Aqueous media results
In principle, 2-BrPA can be made from LA via nucleophilic substitution of the hydroxyl group by
bromide. A typical protocol would include refluxing the alcoholic substrate with aqueous hydrobromic
[25]
acid (HBr(aq)
)
. Indeed, the formation of 2-BrPA from LA and HBr(aq) has been first described in 1864
[26]
by Kekulé. In our first experiments, we applied lactide to form 2-BrPA in the presence of HBr(aq) at
elevated temperatures (see Scheme 1). Lactide can be seen as two lactic acid (LA) equivalents and was
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
4
used as an alternative substrate because it does not contain water. Fast lactide hydrolysis and
consequently LA formation was observed in aqueous HBr solution and even in bromination media with
lower water content (zwitterion-based HBr carriers). Heating the reaction mixture to 110 °C for 5 °s
1
caused formation of 2-BrPA from lactide as proven via H NMR spectroscopy (see Supporting
Information).
Scheme 1: Observed reaction mechanism of lactide in HBr(aq) at elevated temperatures.
However, it is challenging to produce 2-BrPA from LA derivatives and HBr(aq) in high selectivity as
substrate decarbonylation and self-oligomerization / polymerization reactions predominate. The
postulated reaction network of the aqueous bromination system is shown in Scheme 2. Enormous mass
loss over longer reaction times and significant evolution of gas above reaction temperatures of 100°C
result from the strongly competing decarbonylation pathway. Gaseous by-products (acetaldehyde and
carbon monoxide) were detected in our set-up by off-gas analysis. Polymerization has been verified by
precipitation of black and amorphous solid. Even under optimized reaction conditions, namely 5 h,
1
20 °C, and a molar ratio of LA:HBr = 1:3, selectivity towards 2-BrPA (S2BrPA) was below 50%. Note,
that both decarbonylation as well as (poly)condensation produce stoichiometric amounts of water, which
when added to the water in the aqueous bromination agent (HBr(aq), 48 wt% in water), limit the
equilibrium conversion to 2-BrPA. Under optimized conditions, the yield of 2-BrPA (Y2BrPA) that could
be realized was approximately 25%.
Scheme 2: Postulated reaction network in the aqueous reaction medium showing the desired bromination (mid) and
both side-reactions, namely substrate decarbonylation (top) and polymerization (bottom).
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
5
To overcome the limitations of LA bromination with HBr(aq), we decided to investigate ammonium-
[23]
based zwitterions as HBr carriers and brominating agents. The applied zwitterionic carrier molecule
is loaded with HBr by protonation of the sulfonate group, thus forming an acidic bromide IL. This IL-
based bromination system provides several benefits compared to HBr(aq): The bromide anion of the
[23]
acidic bromide IL appears to be more nucleophilic than that in pure HBr . Furthermore, due to the
drastically reduced H O content of the brominating agent, the formation of 2-BrPA that releases water
2
as coupling product should be significantly increased. Another very attractive feature of protonated
zwitterion bromides is the low vapor pressure of HBr in these systems allowing for a save handling of
HBr at elevated temperatures. Thus, the zwitterionic HBr carriers combine the roles of solvent, proton
source, buffer, and brominating agent within one substance.
3
The general concept of applying SO H-functionalized bromide ionic liquids for a convenient and
efficient production of 2-BrPA from LA is illustrated in Scheme 3. Note that the zwitterion serves as
HBr carrier and its chemical structure remains unchanged over the course of the reaction. Therefore,
successful reloading and reuse of the salt over several bromination cycles is expected and will be
demonstrated in this paper.
Scheme 3: LA bromination cycle using tailor-made zwitterionic HBr carrier.
Screening of HBr-carrying zwitterions
To start our experimental work with HBr-loaded zwitterions as LA bromination agents, we tested
different zwitterion structures to identify structural requirements for this particular application (see
Table 1).
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
6
Table 1: LA bromination using different brominating agents: comparison of aqueous HBr (48 wt%) and different
SO H-functionalized bromide ionic liquids.
3
[
a]
[a]
[a]
Entry
HBr source
HBr(aq)
X
LA / %
Y
2-BrPA / %
S
2-BrPA / %
1
2
3
4
40
20
48
54
0
50
> 99
78
[MIMBS]Br
[PyrBS]Br
48
69
[PBu
3
BS]Br
oligomerization
0
Reaction Conditions: 0.05 mol lactide, 0.30 mol HBr source, 120°C, 5 h, ambient pressure; [MIMBS]Br = 1-(4-butane sulfonic
3
acid)-3-methyl imidazolium bromide; [PyrBS]Br = 1-(4-butanesulfonic acid) pyridinium bromide; [PBu BS]Br = Tri-n-butyl-
ꢂ
ꢃ,ꢄꢅꢂꢃ,ꢆ
1
(
4-butanesulfonic acid) phosphonium bromide; [a] conversion, yield and selectivity determined by H NMR as X
=
ꢁ
,
ꢀ
ꢂ
ꢃ,ꢄ
ꢂ
ꢋ
ꢅꢂꢋ,ꢄ |ꢌꢃ|
ꢂ
ꢋ
ꢅꢂꢋ,ꢄ |ꢌꢃ|
ꢍ
ꢋ
Yꢇ-ꢈꢉꢊꢁ
=
∙
and Sꢇ-ꢈꢉꢊꢁ = ꢂ
∙
=
r p
, respectively; n = moles of reactant; n = moles of product.
ꢂ
ꢃ,ꢄ
ꢌ
ꢋ
ꢃ,ꢄꢅꢂꢃ,ꢆ
ꢌ
ꢋ
ꢎ
ꢃ
The zwitterions that contain nitrogen (entries 2, 3) were active in the bromination of LA towards 2-
BrPA. In contrast to HBr(aq), these ionic liquid HBr carriers proved to be highly selective to 2-BrPA.
The highest S2-BrPA in this first screening was achieved with [MIMBS]Br. With this system, no by-
1
products were observed in H NMR and the mass balance could be entirely closed. In contrast,
phosphonium-based ionic liquids did not show any activity. [PBu
3
BS]Br was inactive in the bromination
1
under standard conditions (120 °C) and only lactic acid oligomers were observed after 5 h in H NMR.
At bromination temperatures above 120 °C, all systems showed an increasing tendency to promote
substrate oligomerization / polymerization, as well as decarbonylation to acetaldehyde and CO.
To further reveal influencing effects on the selectivity and yield of the 2-BrPA synthesis, zwitterion-
derived bromide salts of different lipophilicity and acidity were investigated. The respective results are
shown in Figure 1.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
7
100
8
6
4
2
0
0
0
0
0
Increasing lipophilicity
XLA
[MIMBS]Br
[EIMBS]Br
[BIMBS]Br
[OIMBS]Br
Y2-BrPA
S2-BrPA
100
8
6
4
2
0
0
0
0
0
Increasing acidity
[MIMBS]Br
[MIMPS]Br
[PyrBS]Br
IL bromination agent
Figure 1: Influence of cation lipophilicity (top) and acidity (bottom) of the zwitterion-based bromide IL on 2-BrPA
synthesis; conditions: 12.5 mmol lactide, 75 mmol IL, 90 mol% HBr loading grade of IL, water content of ~ 3 wt%,
5
h, 120°C; [EIMBS]Br= 1-(4-butane sulfonic acid)-3-ethyl imidazolium bromide, [BIMBS]Br= 1-(4-butane sulfonic
acid)-3-butyl imidazolium bromide, [OIMBS]Br= 1-(4-butane sulfonic acid)-3-octyl imidazolium bromide,
[
MIMPS]Br= 1-(3-propane sulfonic acid)-3-methyl imidazolium bromide.
Increasing lipophilicity in the bromide ionic liquid is easily realized by extending the alky chain attached
to the imidazolium cation (Figure 1, top part). While replacing the methyl group in the [MIMBS] cation
by an ethyl group does not influence the bromination activity significantly, the use of [BIMBS]Br
already shows a clearly decreased Y2-BrPA and S2-BrPA. With the very lipophilic [OIMBS]Br as
brominating agent for LA, the activity drops drastically. From these results we conclude that a decreased
polarity of the reaction medium slows the rate of the bromination reaction, probably due to less efficient
charge stabilization during the course of the bromination reaction.
The bottom part of Figure 1 shows the influence of the acidity of the zwitterion-based bromide IL on
[24]
the bromination selectivity and yield. It is known from the literature that the IL acidity increases in
[27]
the following order: [MIMBS]Br < [MIMPS]Br < [PyrBS]Br. We observed a decreasing S2-BrPA as
acidity increased from the mildly acidic [MIMBS]Br to the stronger acids [MIMPS]Br and [PyrBS]Br
(
see Figure 1). This confirmed our assumption that too high acidity is detrimental to S2-BrPA as substrate
decarbonylation and self-oligomerization are favored in strongly acidic media.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
8
The following set of experiments has been carried out using the IL [MIMBS]Br. This selection was
made due to the very attractive performance of this IL in the screening experiments (see Table 1 and
Figure 1), but also based on economic considerations. MIMBS is easily produced in large quantities
from the reaction of two commercial compounds: 1-methyl imidazole and 1,4-butane sultone.
LA bromination using [MIMBS]Br - temperature variation
r
In a first set of experiments, we investigated the influence of the reaction temperature (T ) on the
selectivity of the LA bromination with [MIMBS]Br. The results are shown in Figure 2. Starting at our
initial screening temperature of 120°C with a substrate to IL ratio of 1:3, an IL residual water content of
<
1.5 wt%, and HBr loading of 75 mol%, we achieved Y2-BrPA of 35% and S2-BrPA of approximately 100%
1
within 5 h. No by-products were observed by H NMR and the mass balance was closed. Working at
temperatures lower than 120°C led to a reduced LA conversion (XLA), due to a reduced reaction rate.
After LA bromination in [MIMBS]Br 100°C, we observed Y2-BrPA of only 9%. Interestingly, an increase
r
of T to 140°C was not accompanied by a substantial additional increase in Y2-BrPA (37%). Instead,
decarbonylation of LA was observed at 140°C leading to a decrease in S2-BrPA. Moreover, the formation
of 3-bromopropionic acid (3-BrPA) was observed from an emerging isomerization activity of the
system. Our studies indicate that the so-formed 3-BrPA originates from a two-step isomerization process
including AA formation from 2-BrPA and subsequent addition of HBr to AA to form 3-BrPA. Note that
addition of HBr to AA under the applied reaction conditions forms highly selectively 3-BrPA. Moreover,
heating of 2–BrPA in bromide salts in the absence of HBr forms AA as major compound as reported by
[11]
Terrade et al. . Thus, the combined yield of brominated LA species YX-BrPA (Y2-BrPA + Y3-BrPA) after 5 h
reaction at 140°C increased to 49%, whereas the overall selectivity SX-BrPA decreased to 82%.
r
From our experiments we conclude that 120°C is the optimum T for the selective synthesis of 2-BrPA
from LA in [MIMBS]Br. At this temperature, all side and consecutive reactions are suppressed to a very
large extent and still acceptable reaction rates can be realized.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
9
XLA
Y2
Y3
-BrPA
-BrPA
100
SX-BrPA
8
6
4
2
0
0
0
0
0
1
00
120
140
Temperature / °C
Figure 2: Temperature variation in the 2-BrPA synthesis from lactide using [MIMBS]Br as bromination
agent; conditions: 12.5 mmol lactide, 75 mmol IL, 75 mol% HBr loading grade of IL, water content of < 1.5 wt%, 5 h.
LA bromination using [MIMBS]Br - molar ratio variation
In a second set of experiments, we investigated the influence of the molar ratio LA:IL on the outcome
of the lactide bromination reaction (see Figure 3). As the ionic liquid reaction matrix was prepared with
low initial water content, we assumed that an increasing amount of bromide IL should allow higher
yields in 2-BrPA due to a more favorable position of the bromination/hydrolysis equilibrium.
Consequently, we tested LA:IL ratios from 1:1 to 1:6 to confirm this expectation (see Figure 3). Indeed,
we found increased Y2-BrPA when the LA:IL molar ratio increased from 1:1 (29%) to 1:3 (48%). This
increase in yield goes hand in hand with an increase in selectivity to 2-BrPA as substrate decarbonylation
and self-oligomerization are effectively suppressed at the 1:3 ratio. However, no further improvement
in Y2-BrPA was observed when the LA:IL molar ratio was 1:6. Hence, a LA:IL molar ratio of 1:3 was
found ideal for the bromination of lactide with [MIMBS]Br and is used in the following investigations.
The decreased S2-BrPA in the bromination experiment with an LA:IL ratio of 1:1 is assumed to result from
non-hydrolyzed substrate (lactide) and comparably high substrate concentration. The low amount of
water in the reaction medium in this experiment is insufficient for complete lactide hydrolysis and the
remaining intermediate may lead to additional bromination and oligomerization by-products.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
0
Figure 3: Concentration-dependent 2-BrPA synthesis with [MIMBS]Br; conditions: X mmol lactide, 75 mmol IL,
90 mol% HBr loading grade of IL, water content of ~ 3 wt%, 5 h, 120°C.
~
Influence of water
The following experiments aim to shed more light on the role of water in the lactide bromination using
MIMBS]Br. In all experiments HBr was added as 48 wt% aqueous solution to the zwitterion followed
[
by removal of water via azeotropic distillation (see Experimental Section for details) to defined water
and HBr contents (see below).
After this procedure, the residual water content in the IL was monitored by Karl-Fischer titration.
Moreover, acid-base titration of the removed water was carried out to determine the loss of HBr from
the IL during water evaporation (see Experimental Section for details).
To study the influence of water more systematically, two different sets of experiments were performed:
First, we prepared four samples of pre-dried [MIMBS]Br (75 mmol MIMBS, HBr loading grade:
7
5 mol%, ~3 wt% initial water content) and added varying amounts of additional H
The results of these experiments are shown in Figure 4 (top). They clearly confirm that the presence of
increasing amounts of H O negatively influences the bromination reaction. The more H O added, the
lower the Y2-BrPA after 5 h of reaction time was. An addition of 4 g (17.1 wt%) of H O, for instance, led
to a significant drop of Y2-BrPA to 14%, compared to Y2-BrPA of 37% obtained by a water addition of only
2
O (0.5 to 4.0 g).
2
2
2
0
.5 g (3.8 wt%). In all of these experiments, an exceptional S2-BrPA could be realized with no detectable
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
1
formation of by-products. Therefore, the presence of large amounts of water does not affect the
selectivity towards 2-BrPA.
In the second set of experiments, we varied the drying times of the initial HBr-zwitterion solution to
adjust the residual water content of the IL. The residual water content of the brominating reagent was
monitored by the amount of trapped water in the Dean-Stark apparatus and the subsequent Karl-Fischer
2
titration of the prepared ILs. The results of the LA bromination with [MIMBS]Br of different H O
content produced by this loading method are shown in Figure 4 (bottom). In contrast to the results from
the first set of experiments, no significant decrease of Y2-BrPA was observed, although the residual water
content tripled along this series. It is noteworthy that the ILs used in these experiments had a much
higher HBr-loading grade of approximately 90 mol% (determined via acid-base titration of collected
water) resulting from shorten drying times. From the results, we conclude that the HBr loading of the
zwitterion has a dominating influence on the resulting Y2-BrPA over the residual water content of the
reaction matrix. Hence, to obtain an optimum brominating reagent for LA, the water content of
[
MIMBS]Br should be as low as possible to overcome the equilibrium-limiting influence. High loading
grade of HBr on the zwitterion is even more important as the detrimental effect of water is much less
pronounced for systems with high HBr concentrations
.
100
8
6
4
2
0
0
0
0
0
75 mol% HBr loading grade of IL
3.8
5.9
10.1
13.7
17.1
XLA
20
0
5
10
15
Y
2
-BrPA
S2-BrPA
100
8
6
4
2
0
0
0
0
0
90 mol% HBr loading grade of IL
3.5
5.5
7.5
12.5
0
5
10
15
20
H O content of [MIMBS]Br / wt%
2
Figure 4: Influence of water content on 2-BrPA synthesis with [MIMBS]Br. Varying amounts of H
2
O added prior to
bromination after complete drying procedure (top) and varied residual H O content by incomplete drying procedure
2
(
bottom). conditions: 12.5 mmol lactide, 75 mmol IL, 5 h, 120°C.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
2
Then, we attempted to increase the HBr loading to 100 mol% while keeping the water content of the
system to a minimum. In the optimized HBr loading procedure, the MIMBS zwitterion was loaded with
HBr(aq) and subsequently dried at 100°C for 16 h to a residual water content below 1.5 wt%. The
resulting HBr loading grade was determined via acid-base titration. HBr loss during the entire drying
procedure corresponded to 24 mol% of the added HBr. Compensation of this loss was realized by adding
again HBr in the form of its aqueous solution. The resulting IL contained 7.5 wt% of water and a formal
HBr loading of 100 mol% (every sulfonic acid group protonated by HBr). By adding more aqueous HBr
to the dried system, HBr loadings of 133 mol% were realized resulting in a water content of 14 wt% in
this particular case. The results obtained with the [MIMBS]Br with different degrees of HBr loading
and water have been compared under standard reaction conditions (120°C, 5h) and the corresponding
results are shown in Figure 5.
XLA
Y2
-BrPA
S2
-BrPA
100
20
H O content
2
8
6
4
2
0
0
0
0
0
16
12
8
4
0
HBr loading grade of IL bromination agent [MIMBS]Br
Figure 5: Influence of HBr loading grade and water content on 2-BrPA synthesis with [MIMBS]Br.
conditions: 12.5 mmol lactide, 75 mmol IL, 5 h, 120°C. IL loading grade varied by preparation method (1, 2) and
addition of HBr(aq) after drying procedure (3, 4).
Increasing the HBr loading grade from 75 (Figure 5, entry 1) to 90 mol% (entry 2) led to an increase of
2
Y2-BrPA from 35 to 48% despite the higher H O content of the higher-loaded reaction matrix. The fully-
loaded IL (entry 3) achieved an even higher Y2-BrPA of 60% with a S2-BrPA of approximately 100%. No
1
side-products were observed by H-NMR spectroscopy and the mass balance was closed. However,
over-saturation of [MIMBS]Br (entry 4) did not result in higher 2-BrPA yield and significant lactide
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
3
decarbonylation to acetaldehyde and CO was observed. This observation is attributed the fraction of
free HBr” (resulting from over-saturation of the zwitterion), increasing the acidity of the reaction
“
medium and therefore decreasing S2-BrPA
.
Influence of reaction time
As the next step, we were interested to optimize the reaction time for the lactide bromination reaction.
So far, all experiments were conducted for 5 h. For the time variation experiments, fully loaded
[
MIMBS]Br (100 mol% HBr loading, 7.5 wt% water) was used at 120°C with a molar ratio of LA:IL
of 1:3. The results are shown in Figure 6.
XLA
Y2-BrPA
Y3-BrPA
SX-BrPA
100
8
6
4
2
0
0
0
0
0
1
3
5
8
24
Reaction time / h
Figure 6: Time-dependent 2-BrPA synthesis with [MIMBS]Br Five independent bromination experiments with
different reaction times. conditions: 12.5 mmol lactide, 75 mmol IL, full HBr loading grade of IL by compensating
HBr lost during drying procedure, IL water content of 7.5 wt%, 120°C.
Our results indicate that reaction times longer than 5 h do not significantly increase the 2-BrPA yield.
Instead, lactide conversion increases only slightly at prolonged reaction time combined with an
increasing amount of side products formed. Interestingly, after 24 h reaction time also some 3-BrPA is
found in the reaction solution (3%). This indicates that over long reaction times some of the 2-BrPA
product forms AA by dehydrobromination followed by hydrobromination to 3-BrPA even at the mild
reaction temperatures of 120°C.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
4
2
-BrPA isolation from aqueous IL phase via liquid-liquid extraction (LLE)
All experiments so far indicated that the 2-BrPA yield in the [MIMBS]Br reaction system is limited to
around 60% but excellent selectivity could be achieved. A logic concept to drive the reaction to full
conversion of the lactide substrate and 100% 2-BrPA yield was therefore to isolate the 2-BrPA formed
after 5 h from the reaction mixture, regenerate the IL with fresh HBr, and convert the residual lactide
from the first run.
For isolating 2-BrPA from the reaction mixture, liquid-liquid extraction (LLE) was chosen. In-situ LLE
was examined first but led to a decrease in S2-BrPA. Moreover, the realized partition coefficients K2-BrPA
were very low. Therefore, we investigated ex-situ LLE to isolate the formed 2-BrPA from the IL-
containing reaction matrix. To ensure a stable liquid-liquid biphasic system for the extraction
experiment, the IL reaction matrix was quenched with water after the bromination experiment to form
an aqueous IL-containing phase. The added water stayed in the IL phase and was subsequently removed
via azeotropic distillation (see Experimental Section). In the screening experiments for the extraction of
2
-BrPA from the aqueous IL phase, various organic solvents were tested. The results are shown in Table
.
2
Table 2: Results of ex-situ LLE solvent screening*.
b
T of extractor at 1 atm. /
Organic solvent
K
2-BrPA
°
C
1
1
1
2
11
32
56
58
toluene
chloro benzene
bromo benzene
diphenyl ether
chloroform
0.21
0.23
0.17
0.15
1.18
1.82
28.1
6
1
1
41
dibutyl ether (DBE)
1-heptanol
175
*Extraction conditions: 1 mL of quenched product solution, 1 mL of organic solvent, 24 h, room temperature, ambient pressure;
T
b
= boiling temperature; see Supporting Information for details on ex-situ LLE solvent screening.
The determined partition coefficients of 2-BrPA were in the range of 0.15 to 28.1, depending on the
nature of the organic solvent. Whereas aromatics and aryl halides had low extraction ability for 2-BrPA,
chloroform (1.18) and dibutyl ether (1.82) showed reasonable K2-BrPA and can therefore be used for
product isolation. 1-heptanol, however, showed by far the highest K2-BrPA (28.1) of all tested extracting
agents. However, for this solvent, additional LA was detected in the extraction phase (KLA of 3.26)
resulting in a selectivity of 8.62 in favor of 2-BrPA extraction. The other investigated extractors
1
displayed high selectivity towards 2-BrPA, with no LA detectable in the H NMR spectra of the organic
1
layer (details on H NMR measurements see Experimental Section). Hence, 1-heptanol can be used not
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
5
only for product and substrate isolation, but also for possible clean-up procedures of the IL reaction
matrix after the bromination experiment.
Recycling of the zwitterionic reaction matrix
Finally, we investigated the recycling of the zwitterionic reaction matrix under optimized conditions. A
detailed overview of the recycling procedure is given in the Experimental Section. In this recycling
study, we isolated the formed product, 2-BrPA, after the bromination experiment using the two most
attractive extraction solvents from our comparative study (see Table 2), DBE and 1-heptanol. As can be
seen from Figure 7, the isolated amount of 2-BrPA (n2-BrPA) is constant over four bromination cycles
using 1-heptanol for product isolation (n2-BrPA is within the error of the standard experiment, see
Supporting Information), indicating that HBr-reloaded zwitterionic-based molten salts maintain good
activity during recycling. The same very encouraging recycling behavior was found for DBE as an
extracting agent. Here, three recycling procedures were demonstrated. Note that in both recycling series,
a drop of Y2-BrPA was observed with increasing number of bromination experiments, due to incomplete
substrate (LA) extraction from the IL. Non-extracted LA was included into the calculation of Y2-BrPA of
the subsequent experiment. This led to a formally decreasing Y2-BrPA with increasing number of
bromination cycles. However, the constant, isolated amount (moles) of 2-BrPA in the organic layer
clearly showed the recyclability of the brominating agent and reaction matrix over the performed cycles
without any significant loss in HBr loading capacity.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
6
isol. Y2-BrPA with 1-heptanol
isol. Y2-BrPA with DBE
70
2
2
1
1
5
0
5
0
5
isol. n2-BrPA with 1-heptanol
isol. n2-BrPA with DBE
60
50
40
30
20
1
2
3
4
Bromination cycle
Figure 7: The effect of recycled [MIMBS]Br with 1-heptanol and DBE on the isolated n2-BrPA and Y2-BrPA of
bromination of LA to 2-BrPA.
Conclusions
In summary, we developed a novel method for the synthesis of 2-BrPA starting from renewable lactide
using SO H-functionalized bromide ILs. In our proposed concept, a zwitterionic-based molten salt
3
serves as water-free HBr carrier and acidity buffer. When the zwitterionic-based molten salt is loaded
with HBr, the formed ionic liquid has been shown to act as a selective and efficient brominating agent
and reaction matrix (solvent, proton source, and buffer) for the bromination of LA to 2-BrPA.
Especially, imidazole-based ILs showed exceptional selectivity in the synthesis of 2-BrPA from lactide.
The best results were obtained with [MIMBS]Br and [EIMBS]Br reaching 60% yield to 2-BrPA and
1
00% selectivity. This finding is in sharp contrast to the same reaction performed in aqueous HBr
48 wt% HBr) where decarbonylation and self-oligomerization dominated and a maximum yield of only
0% could be achieved under otherwise comparable reaction conditions (120°C, 5 h, and ambient
(
2
pressure). Moreover, product and substrate isolation, as well as brominating agent recycling, have
successfully been demonstrated. Given the unique ability to selectively produce 2-BrPA from bio-
renewable feedstock, we expect this route to contribute substantially to the field of regenerative
production of platform chemicals. Efforts are in progress to apply this new methodology to the synthesis
of bio-AA. Detailed studies on this novel technology for a liquid-phase dehydration of lactic acid to bio-
AA via brominated intermediates are ongoing in our laboratories and will be reported elsewhere. We
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
7
anticipate that the bromination methodology described in this paper will also be transferable to the
selective bromination of other hydroxyl functionalized, complex substrates.
Experimental Section
All used chemicals were purchased from commercial suppliers and used without further purification.
®
Bio-based feedstock lactide, namely PURALACT (L-lactide, polymer grade), was provided by
Corbion.
Preparation of zwitterions
[28]
All zwitterions were prepared via altered synthetic routes according to Yoshizawa et al. and Cole et
[29]
al. . For the preparation of the zwitterion, equimolar amounts of the respective nucleophile (imidazole,
pyridine, phosphine) and the respective sultone (1,4-butanesultone or 1,3-propanesultone) were
dissolved in acetonitrile and refluxed for 48 h. The product precipitated over the course of this reaction.
After cooling to room temperature, the residue was thoroughly washed and dried in vacuum. Products
1 13
were analyzed via H and C NMR spectroscopy. All products were obtained as white powders in very
good yield and excellent purity. Details can be found in the Supporting Information.
Loading of zwitterions with HBr
The ionic liquid bromination medium was prepared from the zwitterion by first mixing equimolar
amounts of the latter (75 mmol) with 48 wt% hydrobromic acid (HBr(aq), 75 mmol) in a 100 mL three-
necked glass reactor. To facilitate stirring and ensure homogeneity of the reaction mixture, two
additional milliliters of water were added. After vigorous stirring for 15 minutes, a clear and colorless
solution was obtained. 50 mL of cyclohexane were added at room temperature and atmospheric
conditions. The biphasic reaction mixture was heated to a temperature of 69.8°C under continuous
stirring with a magnetic stirring bar at a speed of 600 rpm for 16 to 24 h. The protic and HBr-loaded
ionic liquid was isolated by removing the water using a Dean-Stark-apparatus and finally decanting the
cyclohexane phase off after the reactor was cooled down to room temperature. All active HBr-loaded
ionic liquids were obtained as highly viscous and hygroscopic oils.
Characterization of HBr-loaded ionic liquids
The HBr-loading of the ionic liquid was monitored by acid-base titration of the HBr-enriched water that
was removed during the drying procedure. Aqueous NaOH solution (1 M) was dropwise added until the
acidic solution was neutralized. This was followed by color-change of the previously added ethanolic
phenolphthalein indicator solution (0.1 mL). Assuming that no HBr is lost over the gas-phase, acid-base
titration of the trapped water allows to determine the HBr content of the prepared ionic liquid according
to the following equation:
ꢏꢐꢑꢒꢓꢔꢓ ꢕꢖꢗ = ꢏꢘ ꢕꢖꢗ − ꢏꢙꢚꢙꢗꢒꢙꢔꢓ ꢛꢒꢜꢕ
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
8
A reference experiment of direct HBr determination by acid-base titration of the solved and loaded IL
resulted in a fully closed HBr balance (n0 HBr = nloaded HBr + ntitrated NaOH) and therefore confirmed the
developed method.
The residual water content of the IL was analyzed via Karl-Fischer titration (Metrohm 756 KF
Coulometer, the single-component solution used for the analysis was apura® CombiCoulomat fritless
Karl Fischer reagent for coulometric water determination, Merck) in dry methanol. Standard water
contents determined were ≤ 3 wt%.
Bromination reactions with HBr-loaded ionic liquids
The bromination of lactide with zwitterion-based bromide ionic liquids was carried out in a 100 mL
three-necked glass reactor. Lactide (L, L- lactide, polymer grade, Corbion Purac Co., Lenexa, KS) was
added to the HBr-loaded zwitterion in the desired molar ratio. The amount of HBr was readjusted by
addition of aqueous hydrobromic acid (HBr, 48 wt%, Sigma-Aldrich Chemie GmbH, Taufkirchen,
Germany, catalog # 244260), if necessary. The activated reaction mixture was heated to the desired
reaction temperature under continuous stirring with a mechanical overhead stirrer at a speed of 600 rpm.
The reaction mixture was refluxed and all gaseous products were alternatively trapped in a gas sampling
bag for qualitative analysis or collected in a hydrostatic column for gas quantification. After an overall
3
process time of 1 to 24 h, the reaction mixture was quenched with methanol (CH OH, 99.8%, anhydrous,
Sigma Aldrich, Chemie GmbH, Taufkirchen, Germany; catalog # 322415) and the reaction mixture was
1
analyzed via off-line H NMR for quantification of its composition.
Recycling of zwitterions
After completion of the bromination reaction, the reaction mixture was quenched with 10 mL water
instead of the methanol quench mentioned above. When cooled to room temperature, the quenched
reaction medium was extracted (3x20 mL) with an organic solvent to remove the product from the
aqueous phase. The combined organic phases as well as the aqueous phase were quantitatively analyzed
1
by H NMR spectroscopy to give an isolated product yield (YAA, isolated) and to determine the amount of
3
non-isolated C compounds. Finally, the aqueous IL phase was reused for another HBr loading
experiment followed by a new bromination cycle.
Analysis, quantification and calculations
All qualitative and quantitative NMR spectra were recorded on a JEOL ECX 400 MHz instrument with
a sample temperature of approximately 20°C. Chemical shifts were reported relative to the peak of
1
using H-(residual) chemical shifts of the deuterated solvent as a secondary standard and are
Si(CH
3
)
4
1 13
reported in ppm. H scans were conducted with an excitation frequency of 399.72 MHz and 8 scans. C
NMR spectra were recorded with an excitation frequency of 100.51 MHz and 250 scans.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
1
9
Conversion (ꢝ), yield (ꢞ) and selectivity (ꢟ) of all performed experiments were determined via the
1
integrals of the corresponding peaks in the H NMR spectrum, using the following equations (with
ꢠ = reactant, ꢡ = product, ꢢ = stoichiometric coefficient).
ꢥꢤ,ꢦꢅꢥꢤ,ꢧ
ꢣ =
ꢤ
ꢥꢤ,ꢦ
ꢥꢩꢅꢥꢩ,ꢦ |ꢪ |
ꢤ
ꢨꢩ =
∙
ꢥꢤ,ꢦ
ꢪꢩ
ꢥ − ꢥ
|ꢪꢤ| ꢨꢩ
∙ =
ꢩ
ꢩ,ꢦ
ꢫꢩ =
ꢥꢤ,ꢦ − ꢥꢤ,ꢧ ꢪꢩ
ꢣꢤ
The concentration ratio of a species i in the organic phase and the aqueous phase correspond to the
partition coefficient K
i
. The concentration c
i
i
can be obtained from the molar amount n and the volume
1
was obtained from H NMR spectroscopy using an internal standard
of the respective phase, whereby n
i
(
IS) integral for quantification purpose. The selectivity of the extraction agent can be obtained by the
ratio of the respective partition coefficients. The following equations were used to determine the
partition coefficient of the substrate LA (KLA), the product 2-BrPA (K2-BrPA), and the extraction
selectivity towards 2-BrPA (SLLE,2-BrPA).
ꢱꢭꢅꢮꢤꢯꢰ(ꢲꢤꢳ)
ꢱꢭꢅꢮꢤꢯꢰ (ꢴꢵ)
ꢱꢶꢰ(ꢲꢤꢳ)
ꢬꢭꢅꢮꢤꢯꢰ
=
ꢬꢶꢰ =
ꢱꢶꢰ (ꢴꢵ)
ꢬꢭꢅꢮꢤꢯꢰ
ꢫꢶꢶꢷ,ꢭꢅꢮꢤꢯꢰ
=
ꢬꢶꢰ
Acknowledgements
We are very grateful for the excellent scientific and financial support from our industrial collaboration
partner Procter & Gamble. In addition, financial support by the Bundesministerium für Ernährung und
Landwirtschaft through the Fachagentur Nachwachsende Rohstoffe e.V. (FNR, Project No 22009614)
is gratefully acknowledged.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
2
0
References
[
1]
a) M. Avramoff, J. Weiss, O. Schaechter, J. Org. Chem. 1963, 28, 3256; b) D. V. C. Awang, S.
Wolfe, Can. J. Chem. 1969, 47, 706; c) R. Bloch, Synthesis 1978, 1978, 140; d) U. Bora, G.
Bose, M. K. Chaudhuri, S. S. Dhar, R. Gopinath, A. T. Khan, B. K. Patel, Org. Lett. 2000, 2,
247; e) S. Chandrappa, M. Umashankara, K. Vinaya, C. S. A. Kumar, K. S. Rangappa,
Tetrahedron Lett. 2012, 53, 2632; f) H. J. Dauben, L. McCoy, J. Am. Chem. Soc. 1959, 81,
4
1
863; g) R. R. Dim, C. R. Melgarejo, M. T. P. López-Espinosa, I. I. Cubero, J. Org. Chem.
994, 59, 7928; h) C. Djerassi, Chem. Rev. 1948, 43, 271; i) F. L. Greenwood, M. D. Kellert, J.
Sedlak, Org. Synth. Collect. Vol. 1963, 4, 108; j) I. V. Koval’, Russ. J. Org. Chem. 2002, 38,
01; k) A. Wohl, Ber. Dtsch. Chem. Ges. B 1919, 52B, 51.
3
[
2]
a) S. Dunstan, H. B. Henbest, J. Chem. Soc. 1957, 4905; b) R. Heilmann, P. Baret, C. R. Acad.
Sci. C: Sci. Chim. 1968, 267, 579; c) J. D. Prugh, W. C. McCarthy, Tetrahedron Lett. 1966, 7,
1
351; d) P. S. Radhakrishnamurthy, N. C. Sahu, Indian J. Chem. 1981, 20A, 269; e) B. Singh,
R. Srivastava, Curr. Sci. 1985, 54, 415; f) N. Venkatasubramanian, V. Thiagarajan, Can. J.
Chem. 1969, 47, 694.
[
[
[
3]
4]
5]
a) D. D. Agarwal, V. Agarwal, J. Indian Chem. Soc. 1991, 68, 360; b) A. F. Patrocínio, P. J. S.
Moran, J. Organomet. Chem. 2000, 603, 220.
a) N. A. Petasis, I. A. Zavialov, Tetrahedron Lett. 1996, 37, 567; b) C. Thiebes, G. K. Surya
Prakash, N. A. Petasis, G. A. Olah, Synlett 1998, 1998, 141.
a) B. Akhlaghinia, A. Pourali, Turk. J. Chem. 2010, 34, 753; b) D. Azarifar, H. Ghasemnejad
Bosra, M. Tajbaksh, J. Heterocycl. Chem. 2007, 44, 467; c) S. Habibzadeh, H. Ghasemnejad,
M. Faraji, Helv. Chim. Acta 2011, 94, 429; d) A. T. Khan, S. Ali, A. A. Dar, M. Lal, Tetrahedron
Lett. 2011, 52, 5157; e) A. T. Khan, M. M. Khan, A. Adhikary, Carbohydr. Res. 2011, 346, 673;
f) M. A. Pasha, V. P. Jayashankara, Indian J. Chem. 2007, 46B, 1328; g) S. K. Talluri, A.
Sudalai, Org. Lett. 2005, 7, 855.
[
[
[
6]
7]
8]
T. Bastock, M. Holding, Bromination and production techniques for fine chemicals, Contract
Chem Ltd., Prescot, 2004.
Y.-S. Hwang, H. A. Navvab-Gojrati, M. S. Mulla, Journal of Agricultural and Food Chemistry
1
978, 26, 1293-1296.
a) A. Bathe, S. Emmert, B. Helfert, H. Boettcher, Preparation of 5-(1-Piperazinyl)-benzofuran-
-carboxamide 2001; b) P. B. Deshpande, B. B. Boda, S. S. Surti, P. P. Shah, Process for
2
preparation of Tadalafil and its intermediate 2007; c) M. Hans, Phenylaminoacetamides for
regulating plantgrowth 1977; d) S. A. Harris, K. Folkers, Journal of the American Chemical
Society 1939, 61, 1245-1247; e) B. S. Lee, I. K. Park, S. F. Shin, Preparation of 6-hydroxy-2-
oxo-1,2,3,4-tetrahydroquinoline 2000; f) X. T. Li, J. Sui, X. M. Yang, Environment friendly
synthesis of 1-chloroethyl-4-isobutylphenyl ketone 2005; g) C. Loncaric, W. D. Wulff, Organic
Letters 2001, 3, 3675-3678; h) Z. Zhang, Q. Zhang, J. Wang, X. Shi, J. Zhang, H. Song,
Carbohydrate Polymers 2010, 79, 628-632.
[
[
9]
M. A. Kaldrikyan, N. S. Minasyan, R. G. Melik-Ogandzanyan, Russian Journal of General
Chemistry 2016, 86, 305-311.
10]
a) J. R. Dimmock, R. N. Puthucode, J. M. Smith, M. Hetherington, J. W. Quail, U. Pugazhenthi,
T. Lechler, J. Stables, J Med Chem 1996, 39; b) Z. Polivka, J. Holubek, E. Svatek, J. Metys, M.
Protiva, Collect Czech Chem Commun 1984, 49; c) J. Ragavendran, D. Sriram, S. Patil, I. V.
Reddy, N. Bharathwajan, J. Stables, P. Yogeeswari, Eur J Med Chem 2007, 42; d) R. P. Shank,
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
2
1
D. R. Doose, A. J. Streeter, M. Bialer, Epilepsy Res 2005, 63; e) P. Yogeeswari, R.
Thirumurugan, R. Kavya, J. S. Samuel, J. Stables, D. Siram, Eur J Med Chem 2004, 39.
[
[
11]
12]
F. G. Terrade, J. van Krieken, B. J. V. Verkuijl, E. Bouwman, ChemSusChem 2017, 10, 1904-
1
908.
a) M. Kehrer, J. Nagengast, J. Kadar, D. Collias, P. Dziezok, J. Albert, P. Wasserscheid, "Novel
liquid-phase technology for the production of "bio-acrylic acid", 51. Jahrestreffen dt.
Katalytiker, Weimar 15.-17.03. 2017,Oral presentation; b) J. Nagengast, J. Albert, D. Collias,
P. Wasserscheid, "A Liquid-Phase Process for the Sustainable Production of Bio-Acrylic Acid",
5
1. Jahrestreffen dt. Katalytiker, Weimar 15.-17.03. 2017,Poster presentation; c) J. Albert, P.
rd
Wasserscheid, "Novel, selective catalytic routes to organic acids from Biomass", 3
International Symposium on Green & Sustainable Chemistry, La Rochelle 16.-19.05. 2017,
Plenary presentation; d) M. Kehrer, J. Albert, P. Wasserscheid, D. Collias, "Liquid-phase
rd
dehydration of lactic acid towards bio-acrylic acid", 3 International Symposium on Green &
Sustainable Chemistry, La Rochelle 16.-19.05. 2017, Poster presentation; e) J. Nagengast, J.
Albert, P. Wasserscheid, D. Collias, "Nucleophilic Assisted Liquid-Phase Dehydration of Lactic
rd
Acid Derivatives to Bio-Acrylic Acid", 3 International Symposium on Green & Sustainable
Chemistry, La Rochelle 16.-19.05. 2017, Poster presentation; f) J. Kadar, J. Albert, P.
Wasserscheid, D. Collias, "Materials compatability tests and 4x mini plant for bio acrylic acid
rd
synthesis optimization", 3 International Symposium on Green & Sustainable Chemistry, La
Rochelle 16.-19.05. 2017, Poster presentation.
[
13]
a) V. C. Ghantani, M. K. Dongare, S. B. Umbarkar, RSC Advances 2014, 4, 33319-33326; b) J.
H. Hong, J. M. Lee, H. Kim, Y. K. Hwang, J. S. Chang, S. B. Halligudi, Y. H. Han, Applied
Catalysis A: General 2011, 396, 194-200; c) P. Sun, D. Yu, Z. Tang, H. Li, H. Huang, Industrial
and Engineering Chemistry Research 2010, 49, 9082-9087; d) J. Zhang, Y. Zhao, M. Pan, X.
Feng, W. Ji, C. T. Au, ACS Catalysis 2011, 1, 32-41; e) US patents: 8,884,050; 9,422,222;
9
2
,452,967; 9,505,697; 9,611,208; 9,630,901; 9,714,208; f) US patent applications:
015/0031913; 2016/0264507; 2017/0056863; and 2016/0264505.
[
[
14]
15]
F. G. Terrade, B. Verkuijl, E. Bouwman, EP15201469, 2015.
a) IHS Chemicals, Acrylic Acid, https://www.ihs.com/products/chemical-technology-pep-
acrylic-acid-2015.html, accessed 29-09-2017; b) R. Beerthuis, G. Rothenberg, N. R. Shiju,
Green Chemistry 2015, 17, 1341-1361.
[
[
16]
17]
A. Talebian-Kiakalaieh, N. A. S. Amin, H. Hezaveh, Renewable and Sustainable Energy
Reviews 2014, 40, 28-59.
a) C. Hell, Berichte der deutschen chemischen Gesellschaft 1881, 14, 891-893; b) J. Volhard,
Justus Liebigs Annalen der Chemie 1887, 242, 141-163; c) N. Zelinsky, Berichte der deutschen
chemischen Gesellschaft 1887, 20, 2026-2026.
[
[
18]
19]
a) F. A. Castillo Martinez, E. M. Balciunas, J. M. Salgado, J. M. Domínguez González, A.
Converti, R. P. d. S. Oliveira, Trends in Food Science & Technology 2013, 30, 70-83; b) M.
Dusselier, P. Van Wouwe, A. Dewaele, E. Makshina, B. F. Sels, Energy & Environmental
Science 2013, 6, 1415-1442; c) P. Mäki-Arvela, I. L. Simakova, T. Salmi, D. Y. Murzin,
Chemical Reviews 2014, 114, 1909-1971; d) Y. Wee, J. Kim, H. Ryu, Food Technology and
Biotechnology 2006, 44, 163-172.
a) P. Wasserscheid, W. Keim, Angewandte Chemie International Edition 2000, 39, 3772-3789;
b) T. Welton, Chemical Reviews 1999, 99, 2071-2084; c) T. Welton, Coordination Chemistry
Reviews 2004, 248, 2459-2477; d) Y. Beste, M. Eggersmann, H. Schoenmakers, Chemie
Ingenieur Technik 2005, 77, 1800-1808.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
2
2
[
[
20]
21]
a) N. Gupta, G. L. Kad, J. Singh, Journal of Molecular Catalysis A: Chemical 2009, 302, 11-
4; b) N. E. Leadbeater, H. M. Torenius, H. Tye, Tetrahedron 2003, 59, 2253-2258; c) H.-P.
Nguyen, P. Kirilov, H. Matondo, M. Baboulène, Journal of Molecular Catalysis A: Chemical
1
2
004, 218, 41-45; d) B. C. Ranu, R. Jana, European Journal of Organic Chemistry 2005, 2005,
55-758; e) R. X. Ren, J. X. Wu, Organic Letters 2001, 3, 3727-3728.
7
a) R. Appel, Angewandte Chemie International Edition in English 1975, 14, 801-811; b) J.-M.
Mas, P. Metivier, Synthetic Communications 1992, 22, 2187-2191; c) J. D. Pelletier, D. Poirier,
Tetrahedron Letters 1994, 35, 1051-1054; d) M.-F. Pouliot, O. Mahé, J.-D. Hamel, J.
Desroches, J.-F. Paquin, Organic Letters 2012, 14, 5428-5431.
[
[
[
[
[
[
22]
23]
24]
25]
26]
27]
V. Stegmann, K. Massonne, WO2005/026089A2, 2005.
M. Strebelle, WO2012/084624A1, 2012.
H. Li, J. Liu, J. Zhu, H. Wang, Journal of the Korean Chemical Society 2011, 55, 685-690.
J. Houben, T. Weyl, Methoden der organischen Chemie, 4th ed., Thieme, Stuttgart, 1960.
A. Kekulé, Justus Liebigs Annalen der Chemie 1864, 130, 11-31.
a) Y. Wang, X. Gong, Z. Wang, L. Dai, Journal of Molecular Catalysis A: Chemical 2010, 322,
7-16; b) D.-Q. Xu, J. Wu, S.-P. Luo, J.-X. Zhang, J.-Y. Wu, X.-H. Du, Z.-Y. Xu, Green
Chemistry 2009, 11, 1239-1246.
[
[
28]
29]
M. Yoshizawa, M. Hirao, K. Ito-Akita, H. Ohno, Journal of Materials Chemistry 2001, 11,
1
057-1062.
A. C. Cole, J. L. Jensen, I. Ntai, K. L. T. Tran, K. J. Weaver, D. C. Forbes, J. H. Davis, Journal
of the American Chemical Society 2002, 124, 5962-5963.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201702369
2
3
Graphic Abstract
LA bromination cycle using tailor-made zwitterionic HBr carrier.
A convenient and efficient way of synthesizing 2-bromopropionic acid (2-BrPA) from lactide using
zwitterionic HBr carriers is presented. The reaction is performed in ionic liquids (ILs) obtained from
HBr addition to ammonium-based zwitterions, serving as solvent and bromination agent. The character
of the IL reaction matrix enables 2-BrPA synthesis with excellent selectivity. Given the unique ability
to selectively produce 2-BrPA from bio-renewable feedstock, we expect this route to contribute
substantially to the field of regenerative production of platform chemicals.
This article is protected by copyright. All rights reserved.