Stereoselective Synthesis of Trisubstituted Alkenes through Sequential Iron-Catalyzed Reductive anti-Carbozincation of Terminal Alkynes and Base-Metal-Catalyzed Negishi Cross-Coupling

Article abstract of DOI:10.1002/chem.201504049

The stereoselective synthesis of trisubstituted alkenes is challenging. Here, we show that an iron-catalyzed anti-selective carbozincation of terminal alkynes can be combined with a base-metal-catalyzed cross-coupling to prepare trisubstituted alkenes in a one-pot reaction and with high regio- and stereocontrol. Cu-, Ni-, and Co-based catalytic systems are developed for the coupling of sp-, sp²-, and sp³-hybridized carbon electrophiles, respectively. The method encompasses a large substrate scope, as various alkynyl, aryl, alkenyl, acyl, and alkyl halides are suitable coupling partners. Compared with conventional carbometalation reactions of alkynes, the current method avoids pre-made organometallic reagents and has a distinct stereoselectivity. One-pot reaction: A wide range of trisubstituted olefins can be stereoselectively prepared by a sequential iron-catalyzed anti-carbozincation of terminal arylalkynes with alkyl iodides followed by copper-, nickel-, and cobalt-catalyzed cross-couplings with various sp-, sp²-, and sp³-carbon electrophiles, respectively (see scheme; DMA=dimethylacetamide, bipy=2,2-bipyridine, cod=1,5-cyclooctadiene, TMEDA=N,N,N′,N′-tetramethylethylenediamine).

Full text of DOI:10.1002/chem.201504049

DOI: 10.1002/chem.201504049
Full Paper
&
Synthetic Methods
Stereoselective Synthesis of Trisubstituted Alkenes through
Sequential Iron-Catalyzed Reductive anti-Carbozincation of
Terminal Alkynes and Base-Metal-Catalyzed Negishi Cross-
Coupling
Chi Wai Cheung and Xile Hu*[a]
Abstract: The stereoselective synthesis of trisubstituted al-
kenes is challenging. Here, we show that an iron-catalyzed
anti-selective carbozincation of terminal alkynes can be com-
bined with a base-metal-catalyzed cross-coupling to prepare
trisubstituted alkenes in a one-pot reaction and with high
regio- and stereocontrol. Cu-, Ni-, and Co-based catalytic sys-
tems are developed for the coupling of sp-, sp2-, and sp3-hy-
bridized carbon electrophiles, respectively. The method en-
compasses a large substrate scope, as various alkynyl, aryl,
alkenyl, acyl, and alkyl halides are suitable coupling partners.
Compared with conventional carbometalation reactions of
alkynes, the current method avoids pre-made organometallic
reagents and has a distinct stereoselectivity.
can be poor,[1b] and consequently, the regiocontrol relies on
the use of symmetric alkynes or directing groups.[6–8]
Introduction
The stereoselective synthesis of substituted alkenes is a long-
standing goal in organic synthesis.[1] In recent years, transition-
metal-catalyzed cross-coupling has emerged as a straightfor-
ward and versatile method for olefin synthesis.[2,3] This method
is stereospecific; thus, to synthesize stereoselective trisubstitut-
ed alkenes, the corresponding cross-coupling partners, namely
the alkenyl (pseudo)halides or organometallic reagents, need
to have the appropriate stereo-configurations (Scheme 1A).[2,3]
However, stereoselective synthesis of these coupling partners
can be difficult.[4]
We recently reported an iron-catalyzed Z-selective olefin syn-
thesis through the reductive coupling of alkyl halides with ter-
minal aryl alkynes by using zinc as reductant (Scheme 1B).[10]
A
mechanistic study suggested that the alkenylzinc intermediate
1a was formed through Fe-catalyzed anti-selective carbozinca-
Organozinc reagents are compatible with a large number of
sensitive functional groups, which makes them attractive re-
agents in organic synthesis.[5] Alkenylzinc reagents are general-
ly prepared from alkenyl halides by using direct metal insertion
or halogen/metal exchange.[3h,5] Alternatively, they can be pre-
pared from alkynes by transition-metal-catalyzed carbozinca-
tion of alkynes by using organozinc reagents[1,6] or hydrozinca-
tion by using hydride sources.[7]
The carbozincation[1,6] and hydrozincation[7] of alkynes are
usually syn-selective. The anti-carbozincation of alkynes is
rarely reported and in limited cases, is achieved by using al-
kynes bearing directing groups such as carbonyl groups.[8,9]
Moreover, the regioselectivity of the carbozincation of alkynes
[a] Dr. C. W. Cheung, Prof. Dr. X. Hu
Laboratory of Inorganic Synthesis and Catalysis
Institute of Chemical Sciences and Engineering
Ecole Polytechnique FØdØrale de Lausanne (EPFL)
ISCI-LSCI, BCH 3305, 1015 Lausanne (Switzerland)
E-mail: xile.hu@epfl.ch
Scheme 1. A) Synthesis of trisubstitued alkenes by using cross-coupling
methods. B) Synthesis of trisubstituted alkenes by using sequential iron-cata-
lyzed anti-carbozincation of terminal alkynes and base-metal-catalyzed
cross-coupling.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504049.
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tion of the alkyne with alkyl halides. Herein, we show that by
using suitable base metal catalysts (Cu, Ni, Co), such in-situ-
formed alkenylzinc intermediates can be coupled to a wide
range of sp-, sp2-, and sp3-hybridized carbon electrophiles to
afford an array of trisubstituted alkenes[11] with high stereo-
chemical control (Scheme 1B).
However, the yields dropped significantly when a lower load-
ing of the bipy ligand (15 mol%) or CuI (10 mol%) was used
(Table 1, entries 11 and 12). Without CuI, the yield was much
lower (Table 1, entry 13).
The optimized conditions given in Table 1 were then applied
for the cross-coupling of a large number of alkenylzinc re-
agents with bromoalkynes (Scheme 2).[16] Terminal aryl alkynes
containing electron-rich aryl groups, that is, compounds 2a,
2d, 2h, 2l, 2o, and 2q, electron-deficient aryl groups, that is
compounds 2b and 2c and electron-neutral aryl groups, that
is, compounds 2v–2x, could be used to generate the corre-
sponding alkenylzinc reagents for subsequent coupling pro-
cesses. Acyclic (i.e., compounds 2a, 2h, 2j, and 2o) and cyclic
secondary alkyl iodides (compounds 2c, 2l, and 2m), as well
as tertiary alkyl iodides (compounds 2p–2r), served as suitable
reaction partners for the in situ synthesis of alkenylzinc re-
agents, leading to trisubstituted enynes in synthetically useful
yields after the Negishi coupling. The use of primary iodide,
however, only led to a modest yield of the enyne (compound
2n), likely due to the inefficient generation of the alkenylzinc
reagent in the Fe-catalyzed carbozincation step.[10] The scope
of bromoalkynes is also large. Functionalized (bromoethynyl)-
benzenes bearing both electron-donating groups, that is, com-
pounds 2a, 2h, 2o and 2q, and electron-withdrawing groups,
that is, compounds 2b, 2e–2g, 2i–2k, and 2p, at different po-
sitions could be coupled in good yields. Moreover, the cou-
pling reactions tolerated propiolate (compound 2s), propiol-
amide (compound 2t), phenylpropynone moieties (compound
2z), as well as functionalized alkyl (compounds 2u and 2aa)
and carbazole groups (compound 2y). Base-sensitive groups,
including nitro (compound 2g), nitrile (compound 2i), keto
(compounds 2j, 2u, and 2z), ester (compounds 2k and 2s)
and amide groups (compound 2t), were tolerated as well. Sig-
nificantly, the stereoselectivity of the products was high to ex-
cellent (E/Zꢀ9:1 to E/Z>50:1). To the best of our knowledge,
the synthesis of functionalized (E)-enynes is rarely reported.[17]
This protocol would provide a general method to prepare a va-
riety of stereoselective (E)-enynes from readily available alke-
nylzinc reagents and haloalkynes.
Results and Discussion
The cross-coupling of Z-alkenylzinc intermediates with bro-
moalkynes was first studied.[12] Initially, the alkenylzinc reagent
1b was prepared by using the procedure optimized for Z-
olefin synthesis.[10] Because Cu was used as a catalyst in the
cross-coupling reactions of cyclic alkenylzinc reagents with
bromoalkynes,[13,14] we have chosen a Cu catalyst for the analo-
gous coupling of acyclic alkenylzinc reagents. In the presence
of CuCl (20 mol%) and the 2,2’-dibypridyl ligand (bipy,
20 mol%), compound 1b (in excess, up to 1.4 equiv assuming
a 100% yield for the carbozincation) reacted with (bromoethy-
nyl)benzene in tetrahydrofuran at room temperature to give
the (E)-enyne product in 49% GC yield (Table 1, entry 1). The
ligand bipy was superior than other nitrogen- and phosphine-
type ligands (Table 1, entries 2–4). When iodotrimethylsilane
(TMSI, 10 mol%) instead of iodine (2 mol%) was used as the
Zn-activating reagent, the coupling yield was improved to
87% (Table 1, entry 5). Presumably, TMSI readily reacted with
the residual water in the solvent, preserving the alkenylzinc re-
agent for cross-coupling.[15] The loading of the CuCl could be
lowered to 15 mol% without a diminishment of the yield
(Table 1, entry 6). Various Cu catalysts were also screened
(Table 1, entries 7–10), and CuI was found to be the optimal
catalyst to promote the highest yield (95%, Table 1, entry 7).
Table 1. Optimization of the sequential Fe-catalyzed anti-carbozincation
of alkynes and the Cu-catalyzed alkenyl–alkynyl Negishi coupling.[a]
The cross-coupling of alkenylzinc reagents with aryl halides
was then studied by using ethyl 4-bromobenzoate as a test
substrate (Table 2).[12] As Ni catalysts were commonly utilized in
the Negishi couplings of arylzinc reagents with aryl and alkenyl
halides,[3i,18] we have chosen a Ni catalyst for the analogous
coupling of the alkenylzinc reagents. With [Ni(cod)2] (20 mol%)
as the Ni precursor, bipy (20 mol%) was the best ligand
among many nitrogen- and phosphine-based mono- and bi-
dentate ligands for the reaction of compound 1b (1.25 equiv)
with 4-bromobenzoate (1 equiv) (Table 2, entries 1–7), giving
the a-arylated styrene in 64% GC yield (Table 2, entry 5). When
a higher loading of compound 1b (1.4 equiv) was used, the
loadings of [Ni(cod)2] and bipy could be reduced to 10 and
15 mol%, respectively, giving the product in 76% yield
(Table 2, entry 9). [Ni(cod)2] was a better Ni precursor than
other NiII pre-catalysts (Table 2, entries 8 and 12; entries 9 and
11).[19] Without a Ni catalyst, only a low yield was obtained
(Table 2, entry 13).
Entry
Additive
([mol%])
CuX
([mol%])
Ligand
([mol%])
GC yield
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
I2 (2)
I2 (2)
I2 (2)
I2 (2)
TMSI (10)
TMSI (10)
TMSI (10)
TMSI (10)
TMSI (10)
TMSI (10)
TMSI (10)
TMSI (10)
TMSI (10)
CuCl (20)
CuCl (20)
CuCl (20)
CuCl (20)
CuCl (20)
CuCl (15)
CuI (15)
CuBr (15)
CuSCN (15)
CuCN (15)
CuI (15)
bipy (20)
49
46
48
28
87
91
95
83
87
89
79
83
41
phenanthroline (20)
TMEDA (20)
dppe[b] (20)
bipy (20)
bipy (20)
bipy (20)
bipy (20)
bipy (20)
bipy (20)
bipy (15)
CuI (10)
CuI (0)
bipy (20)
bipy (20)
[a] The reaction was based on 0.1 mmol of bromoalkyne. The GC yield
was determined by using n-dodecane as an internal standard. [b] Dppe=
1,2-bis(diphenylphosphino)ethane.
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(compound 3n), as well as aryl
triflate (compound 3s), reacted
equally well at slightly higher
loadings of [Ni(cod)2] (15 mol%)
and bipy (25 mol%). Further-
more, alkenyl bromides also re-
acted to give the a-alkenylated
styrenes in high yields (com-
pounds 3o–3r). Moreover, the
coupling protocol could be ap-
plied for acylation. Thus, carbam-
yl (compound 3t) and aroyl
chlorides (compounds 3u–3w)
reacted at room temperature to
generate the corresponding
enone derivatives. Notably, a vari-
ety of base-sensitive functional
groups, including ester (com-
pounds 3a, 3c, 3d, and 3k),
amide (compounds 3 f and 3t),
nitrile (compound 3g) and keto
groups (compounds 3h, 3l, 3s,
and 3u–3w), were tolerated
under the reaction conditions.
The coupling of the alkenylzinc
reagents with sp2-hybridized
carbon halides was stereospecif-
ic and only single stereoisomers
were formed. As a result, com-
pound 3l, which exhibits an
anti-proliferative activity toward
a number of tumor cell lines,[20]
was readily prepared by using
this protocol, without the prob-
lem of separation from a mixture
of isomeric products as previous-
ly described.
Finally, the cross-coupling of
the alkenylzinc reagents with
alkyl halides was also studied.[12]
As a Co catalyst was applied in
the cross-coupling reactions of
arylzinc reagents with alkyl hal-
ides,[21,22] we have chosen a Co
catalyst for the analogous cou-
pling of the alkenylzinc reagents.
The use of CoBr2 (30 mol%) in
conjunction with two equiva-
lents of N,N,N’,N’-tetramethyle-
thylenediamine (TMEDA) was
Scheme 2. Scope of the Cu-catalyzed alkenyl–alkynyl Negishi coupling of alkenylzinc reagents generated in situ
from the Fe-catalyzed anti-carbozincation of terminal alkynes. The conditions were described in detail in the the
Supporting Information. The yields of the isolated product are shown. [a] Alkyl iodide (3 equiv), Zn (3 equiv), and
TMSI (20 mol%) were used in the first step. [b] Alkyl iodide (2 equiv) and Zn (2 equiv) were used in the first step.
[c] The alkenylzinc reagent (ꢁ1.6 equiv) was used. [d] CuBr2 (10 mol%) was added in the first step. [e] Alkyl iodide
(5 equiv), Zn (5 equiv), and TMSI (30 mol%) were used in the first step. [f] CuI (25 mol%), bipy (35 mol%). [g] CuI
(20 mol%), bipy (30 mol%). DMA=N,N-dimethylacetamide, cod=1,5-cyclooctadiene, Cy=cyclohexyl, Ac=acetyl,
tBu=tert-butyl.
The scope of this Ni-catalyzed alkenyl–aryl Negishi coupling
was studied by using the optimized conditions (Scheme 3).[16]
Both aryl bromides and iodides with varying electronics react-
ed smoothly to give the corresponding a-arylated styrenes in
high yields (compounds 2a–2c, 3e–3i, and 3k). Heteroaryl
bromides, including bromothiophenes (compounds 3d and
3j), bromopyridines (compound 3m) and bromoquionlines
found to promote the reaction of compound 1b with the sec-
ondary alkyl iodide 2-iodooctane, affording a-2-octyl-b-cyclo-
hexylstyrene in 57% GC yield (Table 3, entry 1). In contrast, the
use of derivatives of TMEDA, that is, N,N,N’,N’-tetramethyl-1,3-
propanediamine (TMPDA) and N,N,N’,N’-tetraethylethylenedia-
mine (TEEDA), led to significant drops in the yield (Table 3, en-
tries 2 and 3). The same yield (i.e., 57%) was obtained when
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the loading of CoBr2 was lowered to 20 mol%
(Table 3, entry 4). Co-additives were then screened
(Table 3, entries 6–8), and the additional use of pyri-
dine (3 equiv) was found to be beneficial, giving the
product in 67% yield (Table 3, entry 8). By increasing
the loading of compound 1b to 1.7 equivalents with
respect to 2-iodooctane, a yield of 76% was obtained
(Table 3, entry 9). Under these conditions, a primary
alkyl iodide, that is, 1-iodooctane, reacted equally
well to give a-1-octyl-b-cyclohexylstyrene in 76%
yield (Table 3, entry 9). Without CoBr2, only a trace
amount of product was formed (Table 3, entry 10).
The scope of this alkenyl–alkyl coupling was then
explored (Scheme 4). A variety of acyclic and cyclic,
non-activated secondary alkyl iodides could be cou-
pled in reasonable yields (compounds 4a–4c, 4g,
and 4h). An activated secondary benzyl bromide,
that is, 1-bromo-1-phenylethane, also reacted to give
the desired product (compound 4d). Primary alkyl io-
dides bearing both hydrocarbon skeletons (com-
pounds 4e and 4k) and functional groups such as
chloro (compound 4 f), olefin (compound 4i) and
ester groups (compound 4j) all reacted smoothly to
afford the a-alkylated-styrene
Table 2. Optimization of the sequential Fe-catalyzed anti-carbozincation of alkynes
and the Ni-catalyzed Negishi coupling with sp2-hybridized carbon electrophiles.[a]
Entry
Alkenyl-ZnI
[equiv]
Ni catalyst
([mol%])
Ligand
([mol%])
GC yield
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.4
1.4
1.4
1.25
1.4
[Ni(cod)2] (20)
[Ni(cod)2] (20)
[Ni(cod)2] (20)
[Ni(cod)2] (20)
[Ni(cod)2] (20)
[Ni(cod)2] (20)
[Ni(cod)2] (20)
[Ni(cod)2] (10)
[Ni(cod)2] (10)
[Ni(cod)2] (15)
[Ni(tmeda)(2-tolyl)Cl] (10)
[NiBr2(diglyme)][d] (10)
[Ni(cod)2] (0)
dppe (20)
dppf[b] (20)
PPh3 (80)
xantphos (20)
bipy (20)
phen[c] (20)
2,2’-bis(oxazoline) (20)
bipy (10)
bipy (15)
bipy (15)
bipy (15)
bipy (10)
9
16
22
11
64
18
28
42
76
62
68
27
18
bipy (15)
[a] The reaction was based on 0.1 mmol of bromoalkyne. The GC yield was deter-
mined by using n-dodecane as an internal standard. [b] Dppf=1,1’-bis(diphenylphos-
phino)ferrocene. [c] Phen=1,10-phenantroline. [d] Diglyme=bis(2-methoxyethyl)
ether.
products. 2-(Allyloxy)-3-iodote-
trahydrofuran and 2-(allyloxy)-3-
iodotetrahydro-2H-pyran reacted
to form the products containing
the bicyclic groups (compounds
4l and 4m), suggesting a radical
pathway for the alkyl iodide
cleavage process.[3e] High isomer-
ic ratios (Z/Eꢀ 7:1) were general-
ly observed in the couplings
with alkyl halides. Although
there is room for improvement
in the yields, this protocol repre-
sents, to the best of our knowl-
edge, the first Co-catalyzed cou-
pling of alkenylzinc reagents
with non-activated alkyl hal-
ides.[21]
Conclusion
In conclusion, by combining Fe-
catalyzed anti-carbozincation of
alkynes with base-metal-cata-
lyzed Neigishi coupling, we have
developed an alternative and
general method for the stereose-
lective synthesis of trisubstituted
alkenes.[23] The method employs
catalysts made of base metals
Scheme 3. Scope of Ni-catalyzed Negishi coupling of sp2-carbon electrophiles with in-situ formed alkenylzinc re-
agents. The conditions were described in detail in the SI. Isolated yields were shown. In all products, the ratios of
major to minor isomer were more than 50:1. [a] Ni(cod)2 (15 mol%), bipy (25 mol%). [b] Alkyl iodide (1.8 equiv)
and Zn (1.8 equiv) were used in the first step. [c] rt. [d] Ni(cod)2 (20 mol%), bipy (30 mol%), 808C.
and readily available reagents,
avoiding pre-made organometal-
lic reagents that are used in con-
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Table 3. Optimization of the sequential Fe-catalyzed anti-carbozincation
of alkynes and the Co-catalyzed Negishi-alkyl coupling.[a]
Keywords: carbozincation · catalysis · cross-coupling · iron ·
olefin synthesis · stereoselective
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Entry Alkenyl-ZnI
([equiv])
Co catalyst
([mol%])
Ligand(s)
([equiv])
GC yield
[%]
1
2
3
4
5
6
1.4
1.4
1.4
1.4
1.4
1.4
CoBr2 (30)
CoBr2 (30)
CoBr2 (30)
CoBr2 (20)
CoBr2 (10)
CoBr2 (20)
TMEDA (2)
TMPDA (2)[b]
TEEDA (2)[c]
TMEDA (2)
TMEDA (2)
TMEDA (2)
57
26
37
57
47
49
(+1.4 equiv LiCl)
7
8
9
1.4
1.4
1.7
1.7
CoBr2 2LiCl (30) TMEDA (2)
22
CoBr2 (20)
CoBr2 (20)
CoBr2 (0)
TMEDA (2), py[e] (3) 67
TMEDA (2), py (3)
TMEDA (2), py (3)
[d]
76 (76)
<5 (<1)[d]
10
[a] The reaction was based on 0.1 mmol of bromoalkyne. The GC yield
was determined by using n-dodecane as an internal standard.
[4] The synthesis of substituted and functionalized alkenyl halides and al-
kenylzinc reagents usually involves multistep reactions and the use of
sensitive reagents. For examples of the synthesis of alkenyl halides, see:
C. J. Urch in Comprehensive Organic Functional Group Transformations,
Vol. 2 (Eds.: A. R. Katritzky, O. Meth-Cohn, C. W. Rees), Wiley, New York,
1995, pp. 605–633; for examples of the synthesis of alke-
nylzinc reagents, see reference [1].
[b] TMPDA=N,N,N’,N’-tetramethyl-1,3-propanediamine.
[c] TEEDA=
N,N,N’,N’-tetraethylethylenediamine. [d] 1-Iodooctane was used instead of
2-iodooctane. [e] Py=pyridine.
[5] For selected reviews, see: a) P. Knochel, R. D. Singer, Chem.
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Angew. Chem. 2011, 123, 9968.
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[8] To the best of our knowledge, only one example for the
anti-carbozincation of alkynes was reported; see: J. Maury,
L. Feray, M. P. Bertrand, Org. Lett. 2011, 13, 1884.
[9] For related anti-carbometalation of alkynes, see: a) S. Ma, E.-
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Scheme 4. Scope of the Co-catalyzed alkenyl–alkyl Negishi coupling. The conditions
were described in detail in the Supporting Information. Yields of the isolated products
are shown. [a] Approximately 1.5 equivalents of the alkenylzinc reagent were used.
[b] 1-Bromo-1-phenyethane was used in the second step. [c] Alkyl iodide (1.5 equiv) and
Zn (1.5 equiv) were used in the first step.
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[12] See the Supporting Information for the optimization details.
[13] Cu-catalyzed or -mediated coupling of cyclic alkenylzinc re-
agents with haloalkynes were reported; see: a) H. Heaney, S.
Christie in Science of Synthesis, Vol. 3 (Ed.: I. A. O’Neil),
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ventional carbometalation reactions. The method has a large
substrate scope and a high group tolerance. The high stereo-
selectivity and stereospecifity, as well as an unusual anti-selec-
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see: a) R. Shen, T. Iwasaki, J. Teraob, N. Kambe, Chem. Commun. 2012,
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tivity for the carbozincation, would make the method an at-
tractive tool for stereoselective organic synthesis.
Chem. Eur. J. 2015, 21, 18439 – 18444
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Full Paper
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[16] Initial studies showed that the use of 1.4 equivalents of alkenylzinc re-
agents with respect to organohalide in the second reaction step gave
the trisubsituted products in less than 50% yield of the isolated prod-
ucts. Therefore, we increased the loading of the alkenylzinc reagents to
1.7 equivalents in the substrate-scope study.
ˇ
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[23] We have also studied the cross-couplings of in-situ formed alkenylzinc
reagents with other sp-, sp2-, and sp3-hybridized carbon electrophiles as
shown in Figures S1, S2, and S3 in the Supporting Information. The
yields were generally lower than that shown in the main text. Notably,
the cross-coupling of alkyl-substituted bromoalkynes generally gave
lower product yields. The cross-coupling reactions of other functional-
ized primary and secondary alkyl iodides generally gave lower product
yields.
[18] For recent examples of Ni-catalyzed CÀC cross-coupling reactions, see:
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[19] A new, air-stable NiII pre-catalyst, [Ni(tmeda)(2-tolyl)Cl], has been devel-
oped for various cross-coupling reactions; see: a) J. D. Shields, E. E. Gray,
Received: October 12, 2015
Published online on November 4, 2015
Chem. Eur. J. 2015, 21, 18439 – 18444
www.chemeurj.org
18444
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim