Polar tagging in the synthesis of monodisperse oligo(p-phenyleneethynylene) s and an update on the synthesis of oligoPPEs

Article abstract of DOI:10.3762/bjoc.6.57

One important access to monodisperse (functionalized) oligoPPEs is based on the orthogonality of the alkyne protecting groups triisopropylsilyl and hydroxymethyl (HOM) and on the polar tagging with the hydroxymethyl moiety for an easy chromatographic separation of the products. This paper provides an update of this synthetic route. For the deprotection of HOM protected alkynes, γ-MnO₂ proved to be better than (highly) activated MnO ₂. The use of HOM as an alkyne protecting group is accompanied by carbometalation as a side reaction in the alkynyl-aryl coupling. The extent of carbometalation can be distinctly reduced through substitution of HOM for 1-hydroxyethyl. The strategy of polar tagging is extended by embedding ether linkages within the solubilising side chains. With building blocks such as 1,4-diiodo-2,5-bis(6-methoxyhexyl) less steps are needed to assemble oligoPPEs with functional end groups and the isolation of pure compounds becomes simple. For the preparation of 1,4-dialkyl-2,5-diiodobenzene a better procedure is presented together with the finding that 1,4-dialkyl-2,3-diiodobenzene, a constitutional isomer of 1,4- dialkyl-2,5-diiodobenzene, is one of the byproducts.

Full text of DOI:10.3762/bjoc.6.57

Polar tagging in the synthesis of monodisperse
oligo(p-phenyleneethynylene)s and an update on the
synthesis of oligoPPEs
Dhananjaya Sahoo, Susanne Thiele, Miriam Schulte, Navid Ramezanian
and Adelheid Godt*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, No. 57.
Bielefeld University, Faculty of Chemistry, Universitätsstr. 25,
D-33615 Bielefeld, Germany
doi:10.3762/bjoc.6.57
Received: 02 February 2010
Accepted: 22 April 2010
Published: 01 June 2010
Email:
Adelheid Godt* - godt@uni-bielefeld.de
* Corresponding author
Guest Editor: H. Ritter
Keywords:
© 2010 Sahoo et al; licensee Beilstein-Institut.
License and terms: see end of document.
alkyne protecting group; carbometalation; C–C coupling;
phenyleneethynylene; polar tagging
Abstract
One important access to monodisperse (functionalized) oligoPPEs is based on the orthogonality of the alkyne protecting groups tri-
isopropylsilyl and hydroxymethyl (HOM) and on the polar tagging with the hydroxymethyl moiety for an easy chromatographic
separation of the products. This paper provides an update of this synthetic route. For the deprotection of HOM protected alkynes,
γ-MnO2 proved to be better than (highly) activated MnO2. The use of HOM as an alkyne protecting group is accompanied by
carbometalation as a side reaction in the alkynyl–aryl coupling. The extent of carbometalation can be distinctly reduced through
substitution of HOM for 1-hydroxyethyl. The strategy of polar tagging is extended by embedding ether linkages within the solubil-
ising side chains. With building blocks such as 1,4-diiodo-2,5-bis(6-methoxyhexyl) less steps are needed to assemble oligoPPEs
with functional end groups and the isolation of pure compounds becomes simple. For the preparation of 1,4-dialkyl-2,5-diiodoben-
zene a better procedure is presented together with the finding that 1,4-dialkyl-2,3-diiodobenzene, a constitutional isomer of 1,4-
dialkyl-2,5-diiodobenzene, is one of the byproducts.
Introduction
Oligo(p-phenyleneethynylene)s (oligoPPEs) have been
frequently used as structural units for nanoscopic molecules
because of their geometry and their electronic and photophys-
ical properties [1-19]. For their preparation three widely used
synthetic routes have emerged:
1. The repeating unit by repeating unit approach
(Scheme 1a) with desilylation and coupling of the (func-
tionalized) arylethyne with 1-iodo-4-(2-trimethylsilyl-
ethynyl)benzene as the two repeating steps [6,9,20-24].
The oligomer grows slowly repeating unit by repeating
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Beilstein J. Org. Chem. 2010, 6, No. 57.
unit. In the related bidirectional approach two repeating
units are added in each coupling step (Scheme 1b) [25].
2. The divergent-convergent Moore–Tour-route
(Scheme 2a) [26-29] which employs the diethyltriazenyl
group to mask an iodo substituent [30,31]. 1-(Diethyltri-
azenyl)-4-(2-trimethylsilylethynyl)benzene is the parent
compound. Desilylation and exchange of the triazenyl
substituent for an iodo substituent are the two divergent
steps followed by the alkynyl–aryl coupling, the conver-
gent step. The dialkyltriazenyl group decomposes during
chromatography on silica gel [28].
3. The divergent-convergent route which makes use of the
orthogonality of the two alkyne protecting groups triiso-
propylsilyl (TIPS) and hydroxymethyl (HOM)
(Scheme 2b) [32]. The reaction sequence starts with the
HOM and TIPS protected 1,4-diethynylbenzene 1a1
from which the monoprotected 1,4-diethynylbenzenes 21
and 3a1 are derived by the removal of either the HOM or
the TIPS group. The HOM protected 1,4-diethynylben-
zene 3a1 is coupled with 1,4-diiodobenzene to obtain
aryl iodide 4a2. This is coupled with the TIPS protected
1,4-diethynylbenzene 21 in the convergent step. It has
been shown that HOM can be exchanged for 1-hydroxy-
1-methylethyl (2-hydroxyprop-2-yl, HOP) [33-38].
A rather rarely utilized third divergent-convergent approach
(Scheme 2c) [39-41] relies on the bromo iodo selectivity of the
alkynyl–aryl coupling and bromo iodo exchange via halogen
metal exchange.
The principles underlying these methods have been applied to
building blocks with additional substituents including func-
Scheme 1: Synthesis of oligoPPEs by a unidirectional (a) or bidirec-
tional (b) repeating unit by repeating unit approach. R denotes solubil-
ising substituents.
Scheme 2: Three divergent-convergent routes to oligoPPEs. R
denotes solubilising substituents such as hexyl.
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Beilstein J. Org. Chem. 2010, 6, No. 57.
tional groups as well as to other aromatic building blocks, such only exchanging benzene for diethyl ether, and obtained satis-
as biphenyl [33], bipyridine [36,42], thiophene [36,43,44], fluo- factory results with commercially available active MnO2
rene [45], and triptycene [46], and other shapes, e.g. starlike (Aldrich) [32]. However, the deprotection of the HOM-
compounds [2,7,12,34,37].
protected arylalkynes 1an took several hours, especially when
the reaction was run on larger scale, i.e. with 500 mg or more of
The divergent-convergent route that employs the two orthog- starting material [62]. Even more annoying was that the
onal alkyne protecting groups TIPS and HOM (Scheme 2b) required reaction time varied drastically from one experiment to
does not only allow the fast growth of oligomers – only four another. The best procedure was to add portions of a mixture of
steps for doubling the number of repeating units with two of the MnO2 and KOH in intervals of 15 to 60 minutes until the reac-
four steps being experimentally extremely simple – but is espe- tion was complete. The reaction can be easily monitored by thin
cially satisfying because of a trouble-free separation of the layer chromatography.
desired alkynyl–aryl coupling product and the accompanying
oxidative alkyne dimerization product (Glaser coupling To improve the procedure, we tested the activated MnO2
product). In our experience, under the standard coupling condi- (purchased; Aldrich), highly activated MnO2 (self-made) [63-
tions – i.e. Pd(PPh3)2Cl2, CuI, piperidine, THF, room tempera- 65], BaMnO4 (purchased) [66-68], and γ-MnO2 (self-made)
ture – Glaser coupling is much faster than the alkynyl–aryl [63,64] on 3-(4-bromophenyl)prop-2-ynol in the presence of
coupling. Therefore, even traces of oxygen in the reaction powdered KOH in diethyl ether at room temperature. The reac-
vessel will lead to alkyne dimerization. Furthermore, most tion with γ-MnO2 was the fastest. Even more important,
experimentalists prefer to work up the reaction mixtures under γ-MnO2 when applied to the oligomers 1an proved to be highly
standard conditions which means exposing the reaction mixture reliable in its oxidizing power making it the reagent of choice
to air. Opening the flask will immediately cause any unreacted for the removal of HOM groups. Some experimental results hint
terminal alkyne to undergo Glaser coupling. This is of no at a reduced activity of γ-MnO2 after it was stored for more than
concern provided the alkyne dimer and the alkynyl–aryl half a year in a closed jar under ambient conditions.
coupling product can be easily separated, and this is what the
HOM and related HOP group guarantee since they act as polar Carbometalation
tags for the chromatographic separation. Polar tagging with When we published the synthesis of oligoPPEs via the diver-
HOM [47-49] or HOP [34,42,45,50-57] has been the key to the gent-convergent route which is based on the orthogonality of
successful syntheses of a variety of aryleneethynylene building the alkyne protecting groups TIPS and HOM, we reported the
blocks and oligomers [42,45,47-52] and of oligoeneynes [53] carbometalation product 5a (Scheme 3) which formed as a side
including the natural marine compound callyberyne [54].
product in the coupling of iodo monomer 4a1 with TIPSethyne
[32]. In the original procedure a reaction temperature of 50 °C
Since we disclosed this strategy several years have elapsed was employed. Much later we found that the reaction goes to
during which time we have gained more experience with it, completion even at room temperature. Lowering the tempera-
became aware of some problems concerning it and improved it. ture reduced the amount of the carbometalation product 5a from
Because the strategy has been adopted in whole or in part by 2–16% to 1–5%. Nevertheless, large scale preparative
other groups [33,34,47,49,58,59] and oligoPPEs are still a topic chromatographic separation on silica gel is tedious. Carbometa-
of great interest [1-19], we would like to share our results and lation product 5a and monomer 1a1 have very similar Rf-values
present an update and an extension of our route in this paper. and, unfortunately, the byproduct is eluted first.
There are four issues that we want to address: (1) The type of
MnO2 used for the removal of the HOM group, (2) carbometa- Luckily, contamination of monomer 1a1 with carbometalation
lation, a side reaction when using hydroxymethyl as an alkyne product 5a is of no concern if this material is used to prepare
protecting group, (3) purity of 1,4-dihexyl-2,5-diiodobenzene, the TIPS protected 1,4-diethynylbenzene 21 (Scheme 3). Under
and (4) polar tags in the side chains of building blocks to reduce standard reaction conditions – γ-MnO2, powdered KOH, Et2O,
the number of steps in oligomer synthesis.
room temperature – the alcohol groups of both compounds 1a1
and 5a are oxidized. Whereas the oxidation product of 1a1,
aldehyde 8a1, reacts with KOH to give the ethynyl anion and
formic acid which immediately exchange a proton providing
Results and Discussion
Type of MnO2 used for alkyne deprotection
The original paper on the oxidation-decarbonylation of HOM- deprotected alkyne 21, the oxidation product of 5a, aldehyde 6a,
protected alkynes [60,61] through treatment with MnO2 and is inert under the reaction conditions [69,70]. This finding is
powdered KOH does not contain any details about the type of attributed to the higher energy content and therefore lower
MnO2. We applied this method to the synthesis of oligoPPEs, nucleofugicity of a vinyl anion as compared to an ethynyl
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Beilstein J. Org. Chem. 2010, 6, No. 57.
Scheme 3: Synthesis of the building blocks 11, 21, and 31. The depicted alkene configuration of 5 was chosen assuming a carbometalation process
for the formation of 5 and thus a syn addition of the alkyne onto the hydroxypropyne moiety.
anion. The products, alkyne 21 and the oxidized carbometala-
tion product 6a, are easily separable by chromatography, which
resembles a simple filtration through silica gel because 6a stays
anchored on the solid phase through its polar carbonyl group. In
this way pure alkyne 21 can be obtained even if carbometala-
tion product 5a is present in the starting material.
The case is quite different when monomer 1a1 is used as the
precursor for the HOM protected 1,4-diethynylbenzene 3a1.
Treatment of a mixture of 1a1 and 5a with n-Bu4NF will not
only remove the TIPS group of 1a1 but also the two TIPS
groups of 5a (Scheme 3). The two products are as difficult to
separate as the starting compounds. Furthermore, the ethynyl
groups of both products are expected to have the same reac-
tivity which can make the isolation of pure compounds of
subsequent coupling reactions even more challenging. Finally,
we found that carbometalation not only occurs during the prepa-
ration of monomer 1a1 and its trimethylsilyl (TMS)-analogue
but also, even though extremely rarely, at later stages of the
oligoPPE synthesis. For example, on one occasion we isolated
Scheme 4: Carbometalation, an occasionally detected side reaction.
compound 9a (2%, isolated yield) from the reaction between
alkyne 21 and iodo monomer 4a1 which gave dimer 1a2 as the
major product (79%, isolated yield) (Scheme 4).
The depicted alkene configuration was chosen assuming a carbometa-
lation process and thus a syn addition of the alkyne onto the hydroxy-
propyne moiety.
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In other reactions of this type, the carbometalation product may carbometalation product. Thus, the extent to which carbometa-
have remained undetected due to the limited sensitivity of 1H lation occurs varies with the operator. So far we have no clue
NMR spectroscopy, which we use as a routine method to assess what the relevant factor is. The conclusion is that the alkyne
the composition of the crude product and the chromatographic protecting group HOE reduces the amount of accompanying
fractions, although the characteristic triplet at 6.38 ppm (J = 7 carbometalation product when compared with HOM, however it
Hz) [71] arising from the vinyl proton of the carbometalation does not inhibit it completely.
products is easily observed. If the 1H NMR spectrum displays
the carbon satellites of an aromatic proton signal from the major As expected, the HOE group is as smoothly removed as the
product, the threshold for detection the carbometalation product HOM group through treatment of the protected alkynes 1bn
is as low as 0.5%.
with γ-MnO2 and powdered KOH in diethyl ether at room
temperature. This is illustrated for the conversion of hexamer
While compiling records on carbometalation of hydroxymethyl 1b6 and heptamer 1b7 into the alkynes 26 (98% isolated yield)
protected arylalkynes we never found any evidence for and 27 (90% isolated yield), respectively.
carbometalation of TMS or TIPS protected arylalkynes, even
when conducting the aryl–alkyne coupling at 50 °C [72-75]. Iodination of 1,4-dihexylbenzene
Possibly, the OH-group of the HOM group coordinates to the The preparation of 1,4-dihexyl-2,5-diiodobenzene (10a) by the
alkyne loaded Pd(II)-complex and thus acts as a directing and iodination of 1,4-dihexylbenzene with a mixture of iodine and
rate increasing group. It may as well be that the bulky potassium iodate in HOAc, H2SO4, and water at 70 °C
trialkylsilyl substituents simply act as steric shields for the [32,77,78] gave variable yields and on occasions failed. We
arylalkyne. If the latter is true, then the use of 1-hydroxyethyl obtained 10a much more reliably via iodination with iodine and
(HOE) or HOP instead of HOM as polar protecting groups for periodic acid in HOAc, H2SO4, water, and dichloromethane at
alkynes could prevent carbometalation. Although HOP is a ster- 70 °C [79,80]. Dichloromethane probably acts as a phase
ically more demanding group, we decided in favor of HOE compatibiliser. Nevertheless, the reaction never went to
because the removal of HOP requires refluxing in toluene for completion: In all cases monoiodination product 11a was found
several hours in the presence of sodium hydride or potassium (Scheme 5). Additionally, irrespective of which procedure was
hydroxide [34,36-38,42,50-52,76] whereas we expected that followed, the crude product always contained 1,4-dihexyl-2,3-
HOE could be detached through treatment with γ-MnO2 and diiodobenzene (12a) (ca. 3%), a constitutional isomer of 10a.
powdered KOH in diethyl ether at room temperature, i.e. under The structure elucidation of these byproducts based on 1H NMR
the same, comparatively mild reaction conditions that had been spectra is outlined in Supporting Information File 1.
used for HOM protected alkynes.
For a comparison of the influence of HOM and HOE on the
carbometalation, the iodo monomers 4a1 and 4b1 were coupled
with TIPSethyne in THF and piperidine using Pd(PPh3)2Cl2 and
CuI as the catalysts. A reaction temperature of 40 °C was
Scheme 5: Iodination of 1,4-dihexylbenzene.
chosen in order to boost carbometalation. These two experi-
ments were carried out at the same time, thus providing the best
basis for a comparison. After an aqueous workup, the reaction At least twofold recrystallization is needed to obtain material
products were analyzed by 1H NMR spectroscopy. In both cases which contains less than 0.5% of these byproducts (as deter-
the conversion of 41 was complete and the main component of mined by 1H NMR spectroscopy. The 13C-satellites of the
the crude product was the coupling product 11. The spectra gave signal of the aromatic protons of 10a were used as the refer-
no indication of the presence of carbometalation product 5b ence). Whereas monoiodination product 11a is of minor
whereas carbometalation product 5a (ca. 3%) had formed. concern because it is monofunctional, the constitutional isomer
However, when another member of our group performed the 12a is a severe threat to the structural purity of oligoPPEs and
coupling of TIPSethyne with HOE protected iodo monomer especially polyPPEs. To illustrate this point let us assume that
4b1, he found a trace of carbometalation product 5b (1%; as 10a and thereof derived 1,4-diethynyl-2,5-dihexylbenzene, both
determined by 1H NMR spectroscopy; the characteristic signal contaminated with only 0.1% of the respective constitutional
is the doublet at 6.15 ppm with J = 9 Hz in CDCl3 which is isomers, are polymerized to give a polymer batch with an
assigned to the vinyl proton) in his crude product, although the average polymerisation degree of 1000. The consequence is that
reaction had been performed at room temperature. The same on average each of the polymer chains in this sample will have
co-worker generally obtains a comparatively large amount of a kink, i.e. a severe structural defect.
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Polar tags in the side chain
terminal functional groups, it is tempting to reduce the number
In spite of its efficiency, the divergent-convergent synthesis of of steps through the coupling of a diiodo compound with
oligoPPEs involves considerable effort, especially as a result of oligoPPEs which carry one functional group and have about
the chromatography which is required after each alkynyl–aryl half of the number of repeating units of the target compound.
coupling. In the case of the synthesis of oligoPPEs with To give one concrete example (Scheme 6): Starting from 1a3
Scheme 6: Different routes to compound 14, a representative of the large group of functionalized oligoPPEs.
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Beilstein J. Org. Chem. 2010, 6, No. 57.
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zene 10a (Scheme 6, route A) requires only two alkynyl–aryl
couplings (four steps overall), whereas the alternative
(Scheme 6, route B) via heptamer 1a7 would take three or four
cross coupling reactions (seven or eight steps overall) [81,82].
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very weakly influenced by the number of the non polar
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69.Experimental proof: Carbometalation product 5a was treated with
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The two sets of 1H NMR signals in an intensity ratio of 22:1 for the aryl
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6.47 (d, J = 8.2 Hz, 1 H, C=CH); Characteristic signals of the minor
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71.Characteristic 1H NMR signals of the carbometalation product 9a in
CDCl3: δ = 7.37, 7.31, 7.29, 7.22, 7.17, 6.98 (6 s, 1 H each, ArH), 6.38
(t, J = 7 Hz, 1 H, C=CHCH2OH), 4.06 (t-shaped signal, slightly
broadened, J = 6 Hz, 2 H, CH2OH).
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
72.We know of only two publications that report on carbometalation of
1-aryl-2-trialkylsilylethynes [73,74]. The carbometalation reported in
[73] is possibly induced by the hydroxy group of the hydroxymethyl
substituent in ortho-position to the 2-(trimethylsilyl)ethynyl group. Note
also the related Pd-catalyzed addition of TMSethyne onto
3-(trimethylsilyl)prop-2-ynol giving
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Z-2-(2-trimethylsilylethynyl)-3-trimethylsilylprop-2-enol in [75].
73.Stará, I. G.; Starý, I.; Kollárovič, A.; Teplý, F.; Šaman, D.; Fiedler, P.
Tetrahedron 1998, 54, 11209–11234.
The definitive version of this article is the electronic one
which can be found at:
doi:10.1016/S0040-4020(98)00655-3
74.Batenburg-Nguyen, B.; Ung, A. T.; Pyne, S. G. Tetrahedron 2009, 65,
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79.The use of CCl4 instead of CH2Cl2 as described in [80] for iodination of
1,4-dialkoxybenzene resulted in an even higher conversion. However,
the aromatic substitution reaction was no longer the only occuring
reaction as especially the signals around 6 ppm in the 1H NMR
spectrum of the crude product reveal.
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81.The eight step synthesis is outlined in analogy to the synthesis of the
corresponding oligoPPE diesters in [82]. The eight step route is to be
preferred over the seven step route because of the instability of
oligoPPEs with two unprotected terminal ethyne moieties.
82.Hensel, V.; Godt, A.; Popovitz-Biro, R.; Cohen, H.; Jensen, T. R.;
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