Efficient and sustainable laccase-catalyzed iodination of: P -substituted phenols using KI as iodine source and aerial O2 as oxidant

Article abstract of DOI:10.1039/c9ra02541c

The laccase-catalyzed iodination of p-hydroxyarylcarbonyl- and p-hydroxyarylcarboxylic acid derivatives using KI as iodine source and aerial oxygen as the oxidant delivers the corresponding iodophenols in a highly efficient and sustainable manner with yields up to 93% on a preparative scale under mild reaction conditions.

Full text of DOI:10.1039/c9ra02541c

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Efficient and sustainable laccase-catalyzed
iodination of p-substituted phenols using KI as
iodine source and aerial O2 as oxidant†
Cite this: RSC Adv., 2019, 9, 19549
*
Mark Sdahl, Jurgen Conrad, Christina Braunberger and Uwe Beifuss
¨
Received 4th April 2019
Accepted 27th May 2019
The laccase-catalyzed iodination of p-hydroxyarylcarbonyl- and p-hydroxyarylcarboxylic acid derivatives
using KI as iodine source and aerial oxygen as the oxidant delivers the corresponding iodophenols in
a highly efficient and sustainable manner with yields up to 93% on a preparative scale under mild
reaction conditions.
DOI: 10.1039/c9ra02541c
rsc.li/rsc-advances
For the preparation of iodophenols the electrophilic
aromatic substitution is also the most widely used method. For
Introduction
this purpose, phenols are reacted (a) with iodination agents like
NIS,11a PyICl,11b TICA,11c BMPDCI,11d IPy2BF4,11e BTMA ICl2,11f
I2,11g I2-amine complex,11h I2/AgNO3,11i or I2/KI,11j (b) with I2 in
combination with an oxidant, such as (n-BuPPh3)2S2O8,12a
HIO3,12b K2FeO4/K10,12c H2O2,12d O2/NaNO212e or TICA/SiO2,12f (c)
with an iodide in combination with an oxidant such as NaO-
Cl,13a NaClO2,13b H2O2,13c KClO3,13d NaIO4,13e oxone,13f KIO3,13g
DMSO,13h H2SO413i or tert-butylhypochlorite.13j
Most of these methods have a number of serious disadvan-
tages. Among them are the use of more than equimolar
amounts of iodination agents and/or oxidants. Many of the
reagents employed are acutely toxic, corrosive, explosive and
The iodophenol moiety represents an important structural
motif for many of the nearly 200 iodine-containing natural
products known so far.1 Typical examples include the cytotoxic
tyramine derivative iodocionin (I) from the Mediterranean
ascidian Ciona edwardsii,2a the cytotoxic 60-iodoaureol (II) from
the sponge Smenospongia sp.,2b the antibiotic cyclic depsipep-
tide miuraenamide B (III) from the myxobacterial SMH-27-4 2c
and the thyroid hormones triiodothyronine (IV)2d and thyroxin
(V) (Fig. 1).2d The most prominent non-natural biologically
active iodophenol is amiodarone (VI)3 which is widely used as
an antiarrhythmic drug in the treatment of ventricular and
supraventricular tachyarrhythmias. Iodoaromatics in general
and iodophenols in particular are important substrates for Pd-
catalyzed cross couplings,4 such as the Sonogashira-coupling,5a
the carbonylative Sonogashira-coupling,5b the Negishi-cou-
pling,5c the Suzuki–Miyaura-coupling5d and related reactions,5e
Stille-,5f Hiyama-5g and Heck-couplings.5h Iodophenols can also
be used as substrates for the preparation of organometallics,
such as Grignard reagents, under suitable conditions.6 This is
why the development of selective, efficient and environmentally
benign methods for the preparation of iodoaromatics in general
and iodophenols in particular is of the greatest importance.
Over the years, a number of methods have been developed
for the preparation of iodoaromatics.7 Without doubt, the most
popular is the electrophilic aromatic substitution. Among the
classical methods are also the Sandmeyer reaction,8 the ortho-
lithiation/halogenation9 and the Hunsdiecker reaction.10
Recently, the synthesis of iodoaromatics has been achieved by
methods which are based on sp2 C–H activation.7b
¨
¨
Bioorganische Chemie, Institut fur Chemie, Universitat Hohenheim, Garbenstr. 30,
Stuttgart, D-70599, Germany. E-mail: ubeifuss@uni-hohenheim.de; Fax: +49 711
459 22951; Tel: +49 711 459 22171
† Electronic supplementary information (ESI) available: Experimental data and
copies of the 1H NMR and 13C NMR spectra. See DOI: 10.1039/c9ra02541c
Fig. 1 Important iodinated phenolic compounds.
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oxidizing, while others are commercially not available, expen- accompanied by the reduction of O2 to H2O, which is the only
sive or difficult to prepare. In addition, many iodinations have byproduct of laccase-catalyzed reactions. Laccases with low
to be performed in highly volatile and/or toxic organic solvents. (0.4–0.5 mV), medium (0.5–0.6 mV) and high (0.7–0.8 mV) redox
Most electrophilic aromatic substitutions with I2 or iodide as potentials are known.20a–c By using laccase/mediator systems the
iodine source can only be run successfully in the presence of substrate scope of laccase-catalyzed oxidations can be signi-
heavy metal reagents and/or strong oxidants. All methods which cantly widened.19,20d Among the transformations that can be
make use of I2 as iodine source suffer from the fact, that only catalyzed by laccases on a semi preparative or preparative scale
one iodine atom ends up in the product of the electrophilic are oxidations of several functional groups (CH3 / CHO,21a
aromatic substitution while the other remains unused in the CH2OH / CHO,21b CH2OH / CO2H,21c CH2NH2 / CHO/
reaction medium. Clearly, this results in lower values of atom CO2H21d), the transformation of 1,4-dihydropyridines to pyr-
economy.14 Approaches which are based on the combination of idines21e and oxidative couplings of phenols21f–i and related
I2 and iodides, respectively, as the iodine source, with sustain- substrates21j as well as thiophenols.21k The oxidation of cate-
able oxidants, such as O212e or H2O2,12d,13c are oen hampered by chols and hydroquinones is also known. The resulting o- and p-
their restricted substrate scope12d,e or by the fact that they benzoquinones can be intercepted in different reactions like
require highly acidic conditions.12e,13c As a result, there is great 1,4-additions and Diels–Alder reactions. This approach
demand for iodination methods which are not only highly provides not only access to simple 1,4-adducts22 but also to
selective and efficient but also fulll the requirements of different carbo- and heterocycles.23
sustainable chemistry in order to protect the environment.
Here we show for the rst time, that the laccase-catalyzed
wide range of p-substituted phenolic
Over the last few years, a keen interest in oxidative haloge- iodination of
a
nations, which allow for the use of halides as halogen sources substrates delivers the iodinated products in a highly chemo-
instead of the halogens themselves, has emerged.7d With selective manner on a preparative scale; the dimerization could
respect to sustainability, transition metal- and enzyme- be completely suppressed. Moreover, we will show that the
catalyzed transformations using H2O2 or O2 as oxidants are laccase-catalyzed iodination can be developed to a sustainable
particularly attractive. Enzyme-catalyzed oxidative halogena- iodination method.
tions with H2O2 as oxidant are usually catalyzed by less specic
heme- and vanadium-dependent haloperoxidases, while oxida-
tive halogenations with O2 are mainly catalyzed by more
substrate specic avin-dependent halogenases and non-iron
Results and discussion
Reaction condition optimization
O2-dependant halogenases.15 In this context, studies towards Motivated by our interest in using laccases as catalysts in
the regioselective bromination and chlorination catalyzed by preparative organic chemistry we wondered whether it would be
FAD-dependant tryptophan halogenases16a deserve to be possible to develop a selective, efficient, atom economic and
mentioned since they can be performed on a preparative sca- sustainable iodination of aromatics on a preparative useful
le.16b In contrast, enzyme-catalyzed iodinations have received scale based on the laccase-catalyzed oxidation of alkali iodides
only marginal attention so far. It is known that oxidative to iodine using aerial oxygen as oxidant.
iodinations can be catalyzed by lactoperoxidases,17a–c a chlor-
The optimization of the reaction conditions was performed
operoxidase17d and a horseradish peroxidase.17e However, as using the iodination of vanillin (1a) to 4-hydroxy-3-iodo-5-
good as nothing is known concerning substrate specicity, methoxybenzaldehyde (2a) as a model reaction since vanillin
substrate scope, selectivity, efficiency, scalability and sustain- is a natural product that is manufactured from biomass by
ability of these reactions. First observations concerning the means of an established industrial process on a large scale.24
laccase-catalyzed oxidation of iodide to iodine can be traced Against the background of our experience in the eld of laccase-
back to the reports of Xu17f and Amachi et al.17g Later, Ihssen catalyzed transformations, equimolar amounts of 1a and KI
et al. have reported on the laccase-catalyzed iodination of were stirred with catalytic amounts (225 U) of T. versicolor lac-
phenolic compounds.17h However, a closer look at their results case in the presence of aerial oxygen in acetate buffer (pH
reveals that their method does not allow for the chemoselective 5) : DMSO ¼ 9 : 1 for 48 h at rt (Table 1, entry 1). Under these
iodination of phenols on a preparative useful scale. In most conditions, the desired iodination product 2a was formed in
cases, the formation of the iodophenols was accompanied by only 7% yield. The main product was the dimer 6,60-dihydroxy-
the formation of products resulting from oxidative dimeriza- 5,50-dimethoxy-[1,10-biphenyl]-3,30-dicarbaldehyde (divanillin)
tion. Structure and yields of the iodinated products are difficult (3a). However, the formation of 3a was not surprising, since the
to evaluate since they were not isolated in pure form. Moreover, laccase-catalyzed oxidative dimerization of 1a is known to
the scope of the method was not studied.
deliver 3a.21f Under the conditions presented in Scheme 1, we
Laccases (benzenediol:oxygen oxidoreductase, EC 1.10.3.3) isolated 3a in 91% yield (Scheme 1). To increase the yield of 2a,
are enzymes which are produced by animals, plants, fungi and and to improve the 2a : 3a ratio towards the formation of 2a, the
bacteria.18 Some are commercially available at a reasonable reaction was run with 20 equiv. of KI. This resulted in an
price. Laccases are known to catalyze a number of oxidations increase of the yield of 2a to 24% and an improvement of the
under mild reaction conditions in aqueous solvent systems at 2a : 3a ratio to 20 : 1 (Table 1, entry 2). To further suppress the
pH 3–8 using cheap and environmentally benign aerial oxygen oxidative dimerization, it was decided to keep the actual
as
a
sustainable oxidant.19 The substrate oxidation is concentration of 1a in the reaction mixture as low as possible.
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Table 1 Initial experiments of the laccase-catalyzed iodination of vanillin (1a)a
Entry
KI (equiv.)
Enzyme (U)
Mediator (mol%)
Buffer (mL)
2a : 3a
Yield 2a (%)
1
2
1
225
225
225
225
225
225
225
—
—
—
—
—
ABTS (1)
—
ABTS (1)
ABTS (1)
45
45
45
45
45
90
90
90
1 : 2
7
20
20
20
20
20
20
20
20 : 1
65 : 1
18 : 1
198 : 1
18 : 1
198 : 1
—
24
18
34
46
75
65
—
3b
4c
5
6
7b,c
8
a
2 mmol 1a were reacted. The yields of 2a refer to isolated yields, the ratio 2a : 3a was determined by 1H NMR analysis of the crude product. b 1a in
c
3 mL DMSO was added during 24 h by syringe pump. Initially, 45 U enzyme were added, additional enzyme (180 U) in 3 mL acetate buffer was
added during 24 h by syringe pump.
3a in the crude product (2a : 3a ¼ 18 : 1) (Table 1, entry 6).
However, when the transformation was performed in the pres-
ence of 1 mol% ABTS in 90 mL buffer, and the laccase as well as
the substrate were added gradually, 2a could be isolated in 65%
and the formation of 3a could be almost completely suppressed
(2a : 3a ¼ 198 : 1) (Table 1, entry 7). Despite the fact that under
Scheme 1 Laccase-catalyzed oxidative dimerization of vanillin (1a) to
these conditions the yield of 2a was 10% lower than in the
divanillin (3a).
absence of ABTS, all further experiments were performed in the
presence of 1 mol% ABTS, since this measure guaranteed the
effective suppression of 3a. A control experiment established
that in the absence of laccase and in presence of 1 mol% ABTS
neither 2a nor 3a were formed (Table 1, entry 8). The use of
other cosolvents than DMSO (ethanol, acetone, ethyl acetate)
This was achieved by continuous addition of 1a as a solution in
DMSO (2 mmol 1a in 3 mL DMSO) over 24 h by using a syringe
pump. As expected, the amount of dimer 3a in the crude
product could be decreased considerably (2a : 3a ¼ 65 : 1);
and a phase transfer catalyst (Aliquat 336) had no positive
however, the isolated yield of 2a amounted to only 18% (Table 1,
impact on the yield of 2a.
entry 3). Since it is assumed that the laccase undergoes partial
Table 2 summarizes the experiments performed to decrease
iodination, which results in partial deactivation, parts of the
laccase were added continuously during the reaction. Conse-
quently, only 45 U laccase were added initially and the
the amounts of KI and laccase and to shorten the reaction time.
Particularly gratifying was the observation that the yield of 2a
can be increased by decreasing the amount of KI (Table 2,
remaining laccase (180 U) was added dropwise via syringe pump
entries 1–4). With 3 equiv. of KI, the yield reaches its maximum
during 24 h. This measure resulted in an increase of the yield of
2a to 34%; unfortunately, the ratio of 2a : 3a decreased to 18 : 1
(Table 1, entry 4). It is well known that many laccase-catalyzed
reactions give the products in much higher yields in the pres-
ence of a mediator.19,20d In earlier studies we have established
that ABTS is a particularly suitable mediator for T. versicolor-
catalyzed reactions.21e,k When the laccase-catalyzed iodination
(85%) (Table 2, entry 3). Even with only 1.5 equiv. KI, 2a was
formed in 77% (Table 2, entry 4). With equimolar amounts of
KI, however, the yield of 2a is only 11% (Table 2, entry 5).
Further experiments proved that the amount of laccase can be
reduced signicantly from 225 U to 90 U without any loss of
yield (Table 2, entry 6). Finally, it was revealed that the reaction
time (48 h) can be shortened by a more effective air supply.
of 1a was run in the presence of 1 mol% ABTS, the yield of 2a
When air was bubbled through the reaction solution at a rate of
20 mL minꢀ1, the transformation was already nished aer
increased to 46% and the 2a : 3a ratio improved to 198 : 1
(Table 1, entry 5). Furthermore, it was found that the reaction
volume has a decisive inuence on the yield of 2a. When the
buffer volume was doubled to 90 mL and the reaction was run in
15 h. Under these conditions, the yield of 2a amounted to 77%
with 90 U laccase, and to 85% with a total amount of 135 U
(Table 2, entries 7 and 8).
the absence of ABTS, the isolated yield of 2a could be improved
As part of the optimization, the inuence of the iodide
to 75%. Unfortunately, this was accompanied by an increase of
source and the mediator was studied. It was established that the
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Table 2 Optimization of amount of KI, air supply, amount of enzyme
none of the other mediators tested (violuric acid, 4-acetamido-
TEMPO, 4-methoxy-TEMPO, HOBt, methyl syringate) compa-
rable yields of 2a could be realized (Table 3, entries 6–10). In
addition, it was found (TLC) that the formation of iodovanillin
(2a) was accompanied by considerable amounts of the dimer 3a.
Using 1 mol% HOBt as a mediator, this phenomenon was
studied in some detail. The crude product analysis by 1H NMR
showed that the 2a : 3a ratio amounted to 2.3 : 1 (Table 3, entry
and reaction timea
ꢁ
9). Finally, it was demonstrated that at 50 C, which is close to
the temperature optimum of many laccases,25 only traces of 2a
Add. enzyme
[U], [h]
Yield 2a
(%)
Entry
Equiv. KI
Air
t [h]
1
2
3
4
5
6
7
8
20
5
3
1.5
1
3
1 atm
1 atm
1 atm
1 atm
48
48
48
48
48
48
15
15
180 (44)
180 (44)
180 (44)
180 (44)
180 (44)
45 (44)
45 (5)
65
72
85
77
11
86
77
85b
Table 4 Laccase-catalyzed iodination of 4-hydroxybenzaldehydes
and related compounds 1a–ga
1 atm
1 atm
3
3
20 mL minꢀ1
20 mL minꢀ1
90 (5)
a
2 mmol 1a were reacted in 90 mL buffer. The yields of 2a refer to
isolated yields. Initially, 45 U laccase were added; additional laccase
in 3 mL acetate buffer was added during the time given by syringe
pump. Substrate in 3 mL DMSO was added by syringe pump during
Entry
1
1
a
Laccase (U)
45 + 90
Time (h)
15
Yield product (%)
b
the same time the enzyme was added. The ratio 2a : 3a was
determined by 1H NMR analysis of the crude product (198 : 1).
iodination cannot only be achieved with KI, but also with LiI,
NaI, CsI and NH4I in comparable yields (81–87%) of 2a (Table 3,
entries 1–5). In no case, the formation of 3a could be observed.
The small yield differences suggest that the inuence of the
cation of the iodide source is negligible. In contrast, the
mediator has a decisive inuence on yield and selectivity. With
2
3
4
5
b
c
45 + 90
45 + 90
45 + 90
45 + 90
15
15
48
15
Table 3 Optimization of the iodide source and the mediatora
d
e
Yield 2a
Entry
Iodide source
Mediator
(%)
1
2
3
4
5
6
7
8
9
KI
ABTS
ABTS
ABTS
ABTS
85
81
82
87
81
22
33
29
21b
37
6b
f
45 + 300
45 + 90
144
15
LiI
NaI
CsI
NH4I
KI
KI
KI
KI
KI
ABTS
Violuric acid
4-Acetamido-TEMPO
4-Methoxy-TEMPO
HOBt
7
g
10
Methyl syringate
a
a
2 mmol 1a were reacted in 90 mL buffer. The yields of 2a refer to
2 mmol 1 were reacted in 90 mL buffer. The yields of 2 and 4 refer to
isolated yields. Initially, 45 U enzyme were added, additional laccase isolated yields. Initially, 45 U enzyme were added, additionally laccase in
(90 U) in 3 mL acetate buffer was added during 5 h. Substrate in 3 mL buffer was added during 5 h by syringe pump. Substrate in 3 mL DMSO
DMSO was added by a second syringe pump during the same time the was added by a second syringe pump during the same time the enzyme
b
enzyme was added. In addition to 2a, dimer 3a was detected (TLC). was added. Substrates with one iodination site were reacted with 3
2a and 3a were formed in a ratio of 2.3 : 1 as revealed by 1H NMR equiv. KI, substrates with 2 iodination sites were reacted with 4 equiv.
analysis of the crude product aer ltration.
KI. b Additional enzyme and substrate were added during 15 h.
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were found. Experiments with laccases from other organisms, catalytic amounts of laccase of T. versicolor (45 U + 90 U) and
such as Agaricus bisporus and Pleurotus ostreatus, were also not 1 mol% ABTS in acetate buffer (pH 5) : DMSO ¼ 9 : 1 at rt for
effective.
15 h while bubbling air through the reaction solution. In this
To summarize, the optimization studies showed that best way, 2a was isolated in 85% yield; the corresponding dimer 3a
results were obtained when 1a was reacted with 3 equiv. KI, could not be detected (Table 3, entry 1). It should be mentioned
that the model reaction can easily be upscaled from the 2 mmol
to the 15 mmol scale. In doing so, 2a can easily be synthesized
in gram amounts.
Table 5 Laccase-catalyzed iodination of 4-hydroxyarylketones and
related compounds 1h–pa
Substrate scope
Against this background, scope and limitations of the laccase-
catalyzed iodination of phenolics were studied in greater detail
(Tables 4–6). Initial experiments had revealed that 4-carbonyl- and
4-carboxyl-substituted phenols are the most suitable substrates.
The reactions were performed under the conditions of Table 3,
entry 1. If necessary, the reaction time and/or the amount of lac-
case was increased, and the addition rates of substrate and enzyme
were adapted. Substrates with 2 potential iodination sites were
reacted with 4 equiv. KI. Taking the successful iodination of 1a as
a starting point, we set out to test a number of different 4-
hydroxybenzaldehydes as substrates (Table 4). It was found that
the 3-OMe group in 1a could be replaced easily with an OEt group
(Table 4, entry 2) as well as different halogen atoms (Br, Cl) (Table
4, entries 3 and 4). The experiment with 1e demonstrates that
substrates with an OMe group at C-2 can be iodinated in high
yields, too (Table 4, entry 5). It is remarkable that with the
unsubstituted 4-hydroxybenzaldehyde 1f the formation of the
monoiodinated product could not be detected at all. Instead, the
3,5-diiodo derivative 4f was isolated in 70% (Table 4, entry 6). The
Entry
1
1
Laccase (U)
45 + 90
Time (h)
15
Yield products (%)
h
2
3
4
i
45 + 90
15
j
45 + 180
45 + 180
168
15
Table 5 (Contd.)
k
5
l
45 + 225
45 + 360
24
Entry
1
p
Laccase (U)
45 + 90
Time (h)
24
Yield products (%)
6d
m
168
9
a
2 mmol 1 were reacted in 90 mL buffer. The yields of 2 and 4 refer to
isolated yields. Initially, 45 U enzyme were added, additionally laccase in
buffer was added during 5 h by syringe pump. Substrate in 3 mL DMSO
was added by a second syringe pump during the same time the enzyme
was added. Substrates with one iodination site were reacted with 3
equiv. KI, substrates with 2 iodination sites were reacted with 4 equiv.
7
n
o
45 + 180
45 + 360
60
b
KI. Initially, 1.1 equiv. KI and the substrate were added as solids. No
DMSO was used. 180 U enzyme were added during 12 h. 180 mL
c
8e
120
buffer and 6 equiv. KI were used. 300 U additional enzyme and
d
substrate were added during 5 h. Additional enzyme and substrate
e
were added during 30 h. Additional enzyme and substrate were
added during 20 h.
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Table
6
Laccase-catalyzed iodination of 4-hydroxybenzoic acid
laccase-catalyzed iodination is not restricted to benzene derivatives
as the reaction with 4-hydroxy-1-naphthaldehyde (1g) clearly
proves. The comparative low yield of 2g might be due to the
tendency of the substrate for polymerization (Table 4, entry 7).
Polymerization was also dominant in reactions with phenols
carrying no aldehyde group in p-position, such as 4-bromo-2-
derivatives and related compounds 1q–ta
methoxyphenol,
4-chloro-2-methoxyphenol,
2-methoxy-4-
methylphenol, 4-methylphenol and 2,3-dihydroxybenzaldehyde.
When the aldehyde group in p-position was replaced with an allyl
group and an alkylidene group,21g resp., the exclusive formation of
dimers was observed. Benzaldehydes carrying no hydroxyl group in
p-position, such as 3,4-dimethoxybenzaldehyde and the o-hydroxyl
substituted benzaldehydes 2-hydroxy-1-naphthaldehyde, 2-
Entry
1
1
q
Laccase (U)
45 + 90
Time(h)
36
Yield products (%)
hydroxy-3-methoxybenzaldehyde, 2-hydroxybenzaldehyde,
5-
bromo-2-hydroxybenzaldehyde and 5-chloro-2-
hydroxybenzaldehyde, either didn't react at all or the iodinated
product was only formed in traces. Next, a selection of p-hydrox-
yarylketones was employed as substrates (Table 5). The vanillin
derivative 1-(4-hydroxy-3-methoxyphenyl)ethan-1-one, i.e., acetova-
nillon (1h) could be transformed into the monoiodinated
compound 1-(4-hydroxy-3-iodo-5-methoxy-phenyl)ethan-1-one (2h)
in 73% without any problems (Table 5, entry 1). When the methoxy
group in 1h was replaced with a methyl group, i.e. 1i, the yield of
the monoiodo product 2i was even higher (87%) (Table 5, entry 2).
However, when the methoxy group was replaced with an electron
withdrawing methoxycarbonyl group, i.e. 1j, the yield of 2j dropped
dramatically to only 11% (Table 5, entry 3). C-2 substituted p-
hydroxyarylmethylketones, such as 1k, could be iodinated easily as
well. However, due to two free o-positions adjacent to the hydroxyl
group, the formation of both the monoiodinated and the diiodi-
nated products 2k and 4k took place. Fortunately, the ratio of the
products 2 and 4 can be inuenced by the reaction conditions.
With 4 equiv. KI, the transformation of 1k delivered 2k and 4k with
73% and 13%, resp. When 1k was reacted with 1.1 equiv. KI, the
yield of the monoiodinated 2k could be raised to 78% while the
diiodo compound 4k was formed in only 4% (Table 5, entry 4).
Using the transformation of 1l as an example, it was demonstrated
that the 2 : 4 ratio can also be shied in direction towards the
2b
r
45 + 180
45 + 500
120
48
3c
s
4
t
45 + 270
24
a
2 mmol 1 were reacted in 90 mL buffer. The yields of 2 and 4 refer to
isolated yields. Initially, 45 U enzyme were added, additionally laccase in
buffer was added during 5 h by syringe pump. Substrate in 3 mL DMSO
was added by a second syringe pump during the same time the enzyme
was added. Substrates with one iodination site were reacted with 3
equiv. KI, substrates with 2 iodination sites were reacted with 4 equiv.
b
KI. Additional enzyme and substrate were added during 10 h.
c
Additional enzyme and substrate were added during 30 h.
diiodo product 4. With 4 equiv. of KI, 2l and 4l were isolated with allows the iodination of a wide range of p-hydroxycarbonyl and p-
23% and 64%, respectively. However, when the amount of KI was hydroxyarylcarboxyl compounds under mild reaction conditions.
raised to 6 equiv., the formation of the monoiodinated product 2l By developing suitable reaction conditions, the oxidative coupling
could be suppressed completely. Under these conditions, 4l was could be suppressed completely. Substrates with one iodination
isolated in 84% (Table 5, entry 5). In analogy to 4-hydrox- site produced the monoiodo products with yields up to 87%. When
ybenzaldehyde 4f, the transformation of 1-(4-hydroxyphenol)- substrates with two potential iodination sites were used, in some
propan-1-one (1m) exclusively delivered the diiodo compound in cases the disubstituted products (1f, 1m, 1s) were formed selec-
75% (Table 5, entry 6). Other substrates with 2 potential iodination tively. In other cases (1k, 1l, 1n–p, 1r) mixtures of mono- and
sites (1n–p) produced mixtures of mono- and diiodo products 2 diiodo products were observed. By variation of the reaction
and 4 when reacted with 4 equiv. KI (Table 5, entries 7–9). Finally, it conditions (amount of enzyme and KI, buffer volume, reaction
was studied whether the laccase-catalyzed iodination can also be time, addition rate of enzyme and substrate) the ratio of monoiodo
applied to p-hydroxy-benzoic acid derivatives (Table 6). For this and diiodo products could decisively be inuenced.
purpose, iodination reactions were performed with benzoic acid
esters 1q and 1r, the benzoic acid amide 1s and the benzonitrile 1t
as substrates. In all cases, the expected products, i.e. 2q, 2r and 4r,
Reaction mechanism
4s and 2t, were obtained (Table 6, entries 1–4). It came as a surprise A plausible equation for the laccase-catalyzed iodination of
that in contrast to the methylbenzoate 1r the corresponding benzyl phenolics with KI as the iodine source and oxygen as the
4-hydroxybenzoate and phenyl 4-hydroxybenzoate did not undergo terminal oxidant is presented in Scheme 2. From the equation it
the laccase-catalyzed iodination. The method presented here is clear that only 1 equiv. of KI is required for the iodination and
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that 1 equiv. KOH is formed during the course of the reaction
which results in a pH rise of the reaction solution. It is assumed
that the method can be regarded as an electrophilic aromatic
substitution of the p-hydroxyarylcarbonyls and p-hydroxyar-
ylcarboxyls with elemental iodine as the electrophile (Scheme
3). For simplicity, it is assumed that I2 acts as iodination agent.
ꢀ
However, it cannot be exꢀcluded that I3 is the actual active
iodine species, because I3 is formed rapidly in aqueous solu-
tions containing iodide and iodine.26 The mechanism is sup-
ported by the observation that the regioselectivity of the
iodination is governed by the well-known substituent effects of
the electrophilic aromatic substitution. The molecular iodine
required as electrophile is generated in situ by the laccase-
catalyzed oxidation of KI using oxygen as oxidant. Xu has
demonstrated that the laccase-catalyzed oxidation of iodide can
be enhanced by ABTS.17f Consequently, it is assumed that in the
rst step 2 molecules ABTS undergo oxidation to their corre-
sponding radical cations. The two electrons released from ABTS
reduce one oxygen atom to H2O. The ABTS radical cations on
the other hand oxidize two iodides to I2. The molecular iodine
formed in turn reacts with the phenolic substrate Ar–H to
produce the iodinated product Ar–I as well as HI. It should be
highlighted that in contrast to typical electrophilic substitu-
tions with I2 as reagent, the HI generated during the electro-
philic aromatic substitution is not wasted, but undergoes
a laccase-catalyzed reoxidation to I2. This allows a signicant
reduction of the amount of the iodine source and an improve-
ment of the atom economy from 72 to 85% (Scheme 4). The
atom economy of the laccase-catalyzed reaction can be further
improved by replacing KI with NaI, LiI or NH4I (Table 3, entries
2, 3 and 5).
Even if most of the iodinations were run with a considerable
excess of KI (3 equiv.) (Tables 4–6) we have demonstrated that
the monoiodination can also be performed successfully, when
the amount of KI is reduced from 3 to 1.5 equiv. (Table 2). In one
case, the monoiodination could be achieved with as little as 1.1
equiv. KI (Table 5, entry 4). Further benets of this method are
as follows: it is based on using (a) a biocatalyst which can be
obtained from renewable materials, (b) KI as an easy to handle
iodine source and (c) aerial oxygen as the oxidant to generate I2
from KI. Furthermore, the reactions can be performed under
extremely mild reaction conditions, i.e. in an aqueous solvent
system (pH 5) at room temperature.
Scheme 3 Proposed mechanism of the laccase-catalyzed iodination.
iodinations presented in Tables 4–6 cannot be regarded as truly
sustainable since the amount of waste produced is still too high.
For example, the E-factor27 of the transformation of 1a to 2a
amounts to 31.9 kg kgꢀ1 (Table 7, entry 1). The unfavorable E-
factors are due to (a) the use of an excess of KI (3 equiv. KI for
substrates with one iodination site and 4 equiv. for substrates
with two iodination sites) and (b) the use of large volumes of
solvent. This is why we embarked on further development
towards a synthetic method, which fullls all relevant require-
ments for a green reaction. To reduce the E-factor, a number of
options were available. Among them were the reduction of (a)
the amount of laccase, (b) the excess of KI, (c) the DMSO
concentration, (d) the molarity of the buffer and (e) the che-
moselectivity (iodination versus oxidative coupling) and on
buffer volume itself. However, the focus of our optimizations,
was not only the improvement of the E-factor, but also on high
Towards sustainable laccase-catalyzed iodinations
The next goal was the development of the laccase-catalyzed
iodination towards a truly sustainable synthetic method.
Despite of numerous advantages, the laccase-catalyzed
Scheme 4 Atom economy of the laccase-catalyzed iodination of 1c
Scheme 2 Chemical equation of the laccase-catalyzed iodination.
with (a) I2 and (b) KI/O2.
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Table 7 Experiments towards the optimization of chemical yield, selectivity and E-factor of the model reactiona
Substrate +
Buffer
Buffer vol. Isolated yield
Entry Laccase (U) enzyme addition t (h) KI (equiv.) Time (h) DMSO (vol%) (mol Lꢀ1
)
(mL)
2a (%)
2a : 3a DpH E-factor
1
2
3
4
5
6
7
8
45 + 90
45 + 90
45 + 135
45 + 225
45 + 225
45 + 225
45 + 90
45 + 90
45 + 90
45 + 90
45 + 225
45 + 225
45 + 225
45 + 225
45 + 225
0
5
5
5
5
10
10
5
5
5
3
3
3
3
3
2
3
3
3
3
2
1.5
1.5
1.5
1.5
—
15
15
20
20
20
20
20
20
20
20
20
20
20
24
24
24
10
10
10
2.5
2.5
2.5
10
10
10
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.1
0.2
0.5
0.2
0.2
0.2
0.2
0.2
0.2
90
45
45
45
45
45
45
45
45
45
45
45
45
45
45
45
85
62
85
59
63
70
64
66
58
43
77
68
67
77b
83b
47d
198 : 1
38 : 1
48 : 1
20 : 1
65 : 1
31 : 1
20 : 1 +2.3 18.5
26 : 1 +2.2 18.3
98 : 1 +1.2 21.9
198 : 1 +0.5 33.8
48 : 1
65 : 1
198 : 1
198 : 1
31 : 1
31.9
19.5
13.9
9.6
8.9
6.6
9
10
11
12
13
14
15
16d
5
10
10
10
15
15
10c
15
2.5
2.5
2.5
1.25
0
6.6
7.0
7.2
4.6
2.9
6.7
1.25
198 : 1
a
2 mmol substrate were reacted. 45 U laccase were added initially, additional laccase and substrate were added separately and simultaneously
during the time given via syringe pump. The ratio of 2a and 3a was determined aer ltration and drying of the crude product via 1H NMR.
b
c
d
Isolated yield aer ltration. Enzyme was added during 15 h via syringe pump and substrate was added manually as a solid. 0.75 equiv. I2,
no laccase and ABTS was used.
chemical yield. A number of observations proved to be decisive ratio amounted to 198 : 1. A further improvement of the E-factor
for the optimization process which is summarized in Table 7. It to 2.9 kg kgꢀ1 was possible when the reaction was performed in
was found that (a) the amount of KI can be reduced from 3 to 2 the complete absence of DMSO (Table 7, entry 15). Under these
and 1.5 equiv., resp., (Table 7, entries 5, 6 and 11–15), (b) the conditions, the yield did increase to 83%; however, the 2a/3a
concentration of DMSO can be reduced from 10 vol% to ratio worsened to 31 : 1. Further measures to increase sustain-
1.25 vol% (Table 7, entries 3, 4, 13 and 14) (in some cases the ability but not necessarily the E-factor of the model reaction
cosolvent could be completely omitted) and (c) the buffer related to the reaction mixture workup included the complete
volume can be reduced by 50% (Table 7, entries 1–3). Further- renunciation of organic solvents during workup, a substantial
more, it was found that the dimer formation can be reduced to renunciation of purication by column chromatography and
a minimum by increasing the molarity of the acetate buffer the replacement of Na2S2O7 – which was used to remove
(Table 7, entries 7–10). In this context, the relationship between residual I2 from the reaction mixture – with ascorbic acid (Table
pH and the proportion of dimer should be mentioned. It was 7, entries 14, 15 and Table 8). Additional information and
found that an increase of the pH of the reaction mixture during calculations concerning the greenness and efficiency (TON,
the course of the reaction resulted in an increase of the TOF, STY) of selected reactions are presented in the ESI.† A
proportion of the dimer 3a in the crude product (Table 7, entries control experiment in absence of the laccase with I2 clearly
7–10). To keep the proportion of the dimer as low as possible it revealed that under these conditions the yield is considerable
is necessary to adjust the pH value around pH ¼ 5. Further- lower than under the conditions of the laccase-catalyzed reac-
more, it had to be taken into account that the reduction of (a) tion with KI as iodination agent (Table 7, entry 16).
the amount of KI to 1.5 equiv., (b) DMSO to 1.25 vol% and (c) the
To prove the usefulness of the conditions developed,
buffer volume to half of its initial volume (45 mL) could only be a number of substrates were iodinated according to the condi-
achieved when the amount of laccase was increased to 270 U tions given in Table 7, entries 14 and 15 (Table 8).
and the addition rate of enzyme as well as substrate was
Substrates with a tendency for polymerization (1a, 1b) were
increased to 15 h. Considering all of the above aspects, the E- reacted according to Table 7, entry 14 (Method A). Under these
factor for the transformation of 1a to 2a can be reduced from conditions, the iodination of 1b produced 2b with high selec-
31.9 kg kgꢀ1 (Table 7, entry 1) to 4.6 kg kgꢀ1 (Table 7, entry 14). tivity and 80% yield (Table 8, entry 2). The E-factor for this
Under these conditions, 2a was isolated in 77% and the 2a/3a transformation was 4.14 kg kgꢀ1. A number of substrates with
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Table 8 Sustainable iodination of selected substratesa
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank Mr Mario Wolf (University of Hohenheim) for
recording NMR spectra and Dr Alevtina Mikhael, Dr Claudia
Oellig (University of Hohenheim), and Mr Joachim Trinkner
(University of Stuttgart) for recording mass spectra.
Yield product
(%)
Entry
1
Method
2a : 3a
E-factor
1
2
a
b
c
e
i
A
A
B
B
B
B
77 (2a)
80 (2b)
90 (2c)
90 (2e)
92 (2i)
93 (2k)
198 : 1
98 : 1
198 : 1
198 : 1
198 : 1
198 : 1
4.63
4.14
2.22
2.55
2.49
2.44
Notes and references
3b
4c
5d
6
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2 mmol substrate were reacted in 45 mL buffer. Initially, 45 U enzyme
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In summary, a simple-to-perform and sustainable enzyme-
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