Thiophene ring-fragmentation reactions: Principles and scale-up towards NLO materials

Article abstract of DOI:10.1016/j.tet.2016.12.025

A systematic study on the thiophene ring-fragmentation (TRF) reaction, yielding the Z-isomer of ene-yne type compounds, is presented. The investigations focus on the origins and pathways of potential side-reactions, resulting in an advanced synthetic protocol featuring enhanced selectivity and efficiency. The fragmentation threshold temperatures as well as reaction kinetics have been investigated utilizing inline infrared spectroscopy revealing unexpected results particularly concerning the reaction order (zero-order process). With regard to safety, selectivity, and up-scaling a flow-chemistry procedure for the TRF reaction has been developed. Finally, the technological relevance of the ene-yne structural motif is extended by a new design concept for NLO-chromophores showing the highest second harmonic generation efficiencies reported for these scaffolds.

Full text of DOI:10.1016/j.tet.2016.12.025

Accepted Manuscript
Thiophene ring-fragmentation reactions: Principles and scale-up towards NLO
materials
Daniel Lumpi, Johannes Steindl, Sebastian Steiner, Victor Carl, Paul Kautny, Michael
Schön, Florian Glöcklhofer, Brigitte Holzer, Berthold Stöger, Ernst Horkel, Christian
Hametner, Georg Reider, Marko D. Mihovilovic, Johannes Fröhlich
PII:
S0040-4020(16)31303-5
10.1016/j.tet.2016.12.025
TET 28317
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 September 2016
Revised Date: 10 December 2016
Accepted Date: 12 December 2016
Please cite this article as: Lumpi D, Steindl J, Steiner S, Carl V, Kautny P, Schön M, Glöcklhofer F,
Holzer B, Stöger B, Horkel E, Hametner C, Reider G, Mihovilovic MD, Fröhlich J, Thiophene ring-
fragmentation reactions: Principles and scale-up towards NLO materials, Tetrahedron (2017), doi:
10.1016/j.tet.2016.12.025.
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ACCEPTED MANUSCRIPT
Thiophene Ring-Fragmentation Reactions:
Principles and Scale-Up towards
NLO Materials
Daniel Lumpia,*, Johannes Steindla, Sebastian Steinera, Victor Carla,
Paul Kautnya, Michael Schöna, Florian Glöcklhofera, Brigitte Holzera,
Berthold Stögerb, Ernst Horkela, Christian Hametnera, Georg Reiderc,
Marko D. Mihovilovica, and Johannes Fröhlicha
a Institute of Applied Synthetic Chemistry, Vienna University of Technology,
Getreidemarkt 9/163, A-1060 Vienna, Austria
b Institute of Chemical Technologies and Analytics, Vienna University of Technology,
Getreidemarkt 9/164-SC, A-1060 Vienna, Austria
c Photonics Institute, Vienna University of Technology,
Gußhausstraße 27-29, A-1040 Vienna, Austria
* daniel.lumpi@tuwien.ac.at
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Graphical Abstract
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1) Abstract
A systematic study on the thiophene ring-fragmentation (TRF) reaction, yielding the Z-isomer
of ene-yne type compounds, is presented. The investigations focus on the origins and
pathways of potential side-reactions, resulting in an advanced synthetic protocol featuring
enhanced selectivity and efficiency. The fragmentation threshold temperatures as well as
reaction kinetics have been investigated utilizing inline infrared spectroscopy revealing
unexpected results particularly concerning the reaction order (zero-order process). With
regard to safety, selectivity, and up-scaling a flow-chemistry procedure for the TRF reaction
has been developed. Finally, the technological relevance of the ene-yne structural motif is
extended by a new design concept for NLO-chromophores showing the highest second
harmonic generation efficiencies reported for these scaffolds.
Keywords:
thiophene ring-opening, reaction mechanism, reaction kinetics, inline monitoring, second
harmonic generation
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2) Introduction
The base induced ring-opening reaction of heterocycles is a well-established methodology in
organic chemistry.1 In particular, the organo-metal intermediated ring-fragmentation of
thiophene derivatives, leading to “ene-yne” type compounds, is one of the best-studied ring-
opening reactions.1-3 Early observations of the formation of “unsaturated aliphatic products”
from 3-thienyl-lithium date back to 1962,4 however, the mechanism has not been understood
at that time. The first report on controlled ring-fragmentation was given by Gronowitz et al. in
1969 on the selenophene structure.5 These findings were followed by publications of S.
Gronowitz et al.6 and K. Jakobsen7 demonstrating thiophene ring-opening reactions; similar
studies on benzo[b]thiophene were presented by B. Iddon et al.8 Recent extensions of the
strategy represent double-sided ring-opened species via a tandem fragmentation process.9-11
Thiophene ring-fragmentations (TRF) (Scheme 1) proceed with remarkable stereoselectivity
yielding Z-isomers, selectively;1-3,5-11 alternative approaches to synthesize these scaffolds
typically suffer from poor regio- or/and stereoselectivity.1 Driven by the broad variety of
potential applications, intense research in the development of stereoselective approaches via
e.g. carbo- or hydrothiolation, in order to obtain Z-organylthioenynes but also vinyl sulfides,12-
17 has been reported.
Scheme 1. Generally accepted reaction mechanism of thiophene ring-fragmentation.
The scope of possible modifications, functionalizations (e.g. cycloaddition, Sonogashira-
coupling, Michael-addition, nucleophilic substitution, oxidation) and applications of TRF-
products was demonstrated to be widespread.18 Another important factor for applications,
e.g. in materials science, is the potential to selectively oxidize the alkylthio group.18,19 This
strategy enables to convert the +M- (alkylthio) directly into a –M-substituent (sulfoxide or
sulfone), thus significantly influencing electronic properties.20
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Moreover, ene-yne substructures are found in natural products (e.g. Anthemis species)21-23
and, thus, represent attractive building blocks for total synthesis. Organylthioenynes are also
useful synthons in organic synthesis, as these scaffolds can be utilized as precursors to
enediynes and other functionalized olefins.14 Vinyl sulfides are widely applied in organic
synthesis as versatile intermediates12 and were identified in several biologically active
molecules.12,14,13,24-26 In particular, aromatic vinyl-sulfide derivatives are found in various
pharmaceutically active drugs against important diseases such as Alzheimer’s, Parkinson’s,
diabetes, AIDS, and cancer.14,27,28 For potential pharmaceutical applications the selectivity of
the synthetic approach with respect to double bond geometry is an important issue.
Recently, our group has reported on ene-yne derived nonlinear optical (NLO) materials
capable of second harmonic (SH) generation.29-31 Direct functionalization of TRF-products via
copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)32,33 applying phenylazide yielded
NLO materials featuring twice the SH-efficiency of potassium dihydrogen phosphate (KH2PO4
- KDP).30 Furthermore, replacing sulfur by selenium resulted in 20-fold higher SH-efficiency
due to an increased electron density leading to enhanced hyperpolarizibility.31
Applications in the field of materials science in particular necessitate efficient and reliable
synthetic access to TRF-products. Here, we present a systematic study on the thiophene
ring-opening approach focusing on origins and pathways of potential side reactions. As a
result, an advanced procedure leading to significantly improved Z-selectivity and efficiency is
being developed. We investigated the reaction kinetics of the TRF, applying inline monitoring
via infrared spectroscopy and implemented flow chemistry for safe and convenient scalability
of the process. In addition, the development of an improved design concept for NLO-
chromophores, yielding the highest SH-generation efficiencies reported for TRF-based
products up to date, underlines the technological relevance of ene-yne compounds.
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3) Results and Discussion
3.1) Thiophene Ring-Fragmentation
In the course of our research on NLO materials, utilizing (Z)-trimethyl(4-(methylthio)pent-3-
en-1-inyl)silane (3a, Scheme 2) as an ene-yne scaffold, deviations from the synthetic
protocol30 (e.g. loss of inert atmosphere) resulted in an unexpected E/Z-isomerization of 3a
toward the E-species 3f (typically in the range of 1-5 %). For this reason, the impact of the
reaction components on the isomerization was evaluated. It could be shown that neither the
used dry solvent (Et2O), the reactants (2a, n-BuLi, MeI) nor the organic by-products (n-BuBr)
are associated with this process. However, the addition of LiI, which is formed during
quenching of the TRF reaction using MeI, results in an isomerization of 3a. By evaluating
various salts containing Li+- or I--ions (LiCl, LiBr, LiClO4, LiI, NaI, KI and TBAI – see
Supplementary Data) it was established that the iodide anion is responsible for this side-
reaction. Interestingly, this reaction showed enhanced rates in the presence of oxygen; argon
atmosphere significantly limits this effect.
From these experiments we concluded that the formation of elemental iodine (I2), even if only
present in traces, is the origin of the formation of the E-species. This I2-induced process of
double bond isomerization is well-described in literature.34 Indeed, a control experiment
revealed that the addition of I2 (1 mol%) induces this reaction (Figure 1); full exclusion of light
suppresses the isomerization.
To further quantify this side reaction, 3a and the corresponding E-isomer 3f were subjected
to UV-light assisted isomerization experiments. The reactions were carried out in standard
NMR tubes using an I2 solution in CDCl3 at concentrations of 1.0 mol% and a standard light
source.35 The results for 1.0 mol% I2 are illustrated in Figure 1. The experiment yielded the
same E/Z-ratio starting from both, the pure Z- and E-isomer, indicating that complete
equilibration is reached during the I2-induced isomerization. Additional experiments using
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10.0 mol% I2 and starting material 3a revealed that an equilibrium state between the Z- and
E-isomer is already reached within 15 s of light irradiation
Figure 1. I2-induced isomerization of ene-yne compounds 3a and 3f (1.0 mol% I2 solution in CDCl3);
curve fitting performed using standard exponential fit parameters.
The equilibrium state consists of 16% 3a (Z-isomer) compared to an 84% 3f (E-isomer),
corresponding to the thermodynamic energy level difference between the Z- and the E-
isomer as indicated by DFT calculations. This fact clearly points out the importance of the
TRF approach to obtain the thermodynamically less favored isomer. Moreover, the strategy
potentially allows obtaining the corresponding E-structure in good yields. Indeed, repeating
this experiment on preparative scale (using a 1.0 mol% I2 solution) resulted in 76% of pure
(E)-trimethyl(4-(methylthio)pent-3-en-1-inyl)silane (3f) after column chromatography.
Hence, various alternative methylation sources were assessed. The trials revealed that
iodomethan (MeI) outperforms the applied analogs (trifluoromethanesulfonate (MeOTf),
dimethyl sulfate (Me2SO4) and methyl 4-methylbenzenesulfonate (MeOTs)) clearly with
regard to efficiency and selectivity. Further information on potential side reactions is given in
chapter 2 in the Supplementary Data (acid-induced isomerization pathways).
As a consequence, the second approach was to avoid the formation of I2. On the one hand,
the removal of I- with Ag+-salts (e.g. Ag2CO3) and, on the other hand, the addition of a
reducing agent were attempted for this purpose. In both cases, the formation of E-isomer
was entirely suppressed. Particularly the application of Na2SO3 as the reducing agent prior to
the addition of MeI proved to be advantageous. This new procedure for TRF, also applying
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slightly modified reaction parameters, combines both the prevention of the isomerization and
the ease of workup. In addition to the significant improvement in stereospecificity an
enhanced isolated yield of 86% (vs. 76 - 81% using the old procedure)30 for 3a was obtained,
which shows the efficiency of the protocol.
To demonstrate the scope of the developed protocol, various substrates for TRF reactions
were evaluated (Scheme 2). The modifications of 2a include the introduction of more stable
silyl groups R (from TMS to TBDMS and TIPS) and variation in the substituent R’ in the
thiophene 5-position (from sp3 to sp2 and sp hybridization). The diversity of suitable silyl
groups is an important factor with regard to specific functionalization. The alteration towards
sp2 and sp centers for R’ derives from the current interest in these compounds as organic
functional π-systems (e.g. NLO materials).
Scheme 2. Synthesis of compounds 3a-f; i: HD-reaction; ii: new TRF-protocol; iii: I2-induced isomerization.
Detailed synthetic protocols for the synthesis of precursors 2a-e via Halogen-Dance
reactions36 and TRF towards 3a-e are given in the Supplementary Data. Applying the novel
TRF protocol all ring-opening reactions were accomplished successfully and in good yields of
75–86 % without any formation of E-isomer; the proof for the formation of the Z-isomers has
been given by X-ray diffraction on various examples.37,38 A tendency towards lower yields for
larger silyl groups (3a / 3b / 3c = 86% / 82% / 75%) and an increase in yields for sp to sp2
and sp3 hybridization of R’ (3e / 3d / 3a = 77% / 81% / 86%) has been observed.
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3.2) Kinetic Investigations
Although the TRF reaction has been extensively studied regarding the substrate scope, no
kinetic data is available. Based on previous investigations39 on organo-lithium compounds an
ATR-IR probe was applied for inline reaction monitoring to explore the ring-opening process
under dynamic conditions in order to gain insight on fragmentation threshold temperatures
and reaction kinetics. Recent progress in the development of mid-IR transparent fibres40 and
sensor assembly render it possible to achieve reliable data even under non-isothermal
conditions. This allows for a monitoring of the TRF reaction in a warm-up phase yielding the
on-set temperature of the ring-opening. The inline approach (both in-situ and real-time) is of
critical importance for this study, since alternative techniques typically suffer from sample
alteration during sampling.39
In the initial experiments the fragmentation threshold temperatures were matter of interest.
For this purpose the respective substrates (2a, 2b, 2d, 2e) were lithiated via metal-halogen
exchange using n-BuLi (1.1 eq.) at -60 °C in anhydrous Et2O (0.2 M). The fragmentation of
the TIPS-substituted derivative 2c could not be monitored under the applied conditions due
to the low solubility in Et2O at -60 °C. After completion of the lithiation process the
temperature was raised to ~ 0 °C at a constant rate (0.5 °C / min). Indeed, the formation of
intense new absorption bands, particularly in the fingerprint region (650-900 cm-1), were
observed for all substrates at certain temperatures reproducibly. These bands reveal a
significant correlation to peaks located between 2100-2200 cm-1 (highly specific for C-C triple
bonds), which confirms the onset of the TRF reaction forming the ene-yne moiety. However,
due to the self-absorption of the applied ATR-unit these bands were not utilized for
quantitative analyses. The obtained concentration profiles during the ring-opening of 2a are
exemplarily depicted in Figure 2 (profiles for all fragmentation products are given in the
Supplementary Data). Remarkably, the obtained ring-opening temperatures (defined by a 5%
intensity threshold relative to the baseline) are in contrast to literature values. Whereas
thiophene ring-fragmentations are typically reported to occur at room-temperature,3,1,2 we
observed reaction on-set temperatures of -50 °C, -47 °C and -42 °C for 2a, 2b and 2e,
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respectively. Only the fragmentation of 2d was found to take place at higher temperature (-24
°C), which is attributed to stabilizing effects of the phenyl substituent.
Figure 2. Normalized integrals of selected absorption bands of 3a and temperature gradient during TRF of 2a.
Furthermore, we investigated the TRF of 2a under isothermal conditions (-45 °C, -40 °C and
-35 °C). A linear time dependence was observed for the product formation at all
temperatures (Figure 3) indicating a zero-order reaction, typically found for saturated
catalytic processes. The reaction rates plotted against 1/T also show the linear dependence
required by the Arrhenius equation, confirming this assumption (Supplementary Data). This
finding is in obvious disagreement with the reaction mechanism depicted in Scheme 1, which
implies a first-order reaction. To gain further insights we applied an excess n-BuLi and
altered the concentration (0.13 M) of 2a, however, did not find any significant influence of the
variations on the reaction rate. At this point, the reason for the zero-order kinetics is not
understood and remains to be clarified by future research.
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Figure 3. Normalized integrals of absorption bands at 1249 cm-1 (solid), 854 cm-1 (dashed) and 759 cm-1 (dotted)
of 3a during TRF under isothermal conditions.
Table 1. Isolated yields and fragmentation temperatures of TRF products 3a-e.
Isolated Yielda
[%]
TRF Temperatureb
[°C]
86
-50
3a
3b
82
-47
75
81
77
n.o.c
-24
3c
3d
3e
-42
a i) Et2O (0.2 M), -40 °C, n-BuLi (1.1 eq.),
ii) rt, 30 min,
iii) -40 °C, Na2SO3 (1.2 eq.),
iv) MeI (1.5 eq.), rt.
b Defined by 5% threshold temperature.
c Not observed due to low solubility.
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3.3) Flow Chemistry
Problems associated with solvent interactions, highly exothermic reactions and other safety
issues limit the applicability of organolithium reagents to low temperature regimes.
Unfortunately, the scale-up of cryogenic reactions employing hazardous reagents such as
organometallic compounds under strictly inert conditions tend to be troublesome and error-
prone. However, excellent heat transfer and short residence times (tR) allow those reactions
to be conducted safely in a microflow reactor. Inspired by previous reports on ring-
fragmentation under flow conditions,41 we therefore aimed to incorporate the TRF to an
automated flow process, providing wide scalability and safe operation conditions.
Furthermore, the application of such a microflow reactor guarantees fully inert atmosphere
which is of crucial importance in order to avoid the formation of the undesired E-isomer. Low
fragmentation temperatures observed during IR-experiments allow for short residence times
in a microflow reactor under convenient temperature (Figure 4).
Figure 4. Microreactor setup for continuous-flow experiments.
A stainless steel microreactor was fabricated (Figure 5), consisting of individual pre-cooling
zones for reagents (200 µL volume each), T-shaped mixers and two microfluidic reaction
zones – one for the lithiation (1 mL volume) and one for the quench (1.5 mL volume). In
order to allow reaction temperatures down to -40 °C, a dual-stage Peltier-assisted cooling
module was developed (FlowChiller), and attached to the bottom of the stainless steel
reactor.
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Figure 5. Stainless steel microreactor equipped with pre-cooling zones, a lithiation reaction zone and a quench
reaction zone.
Precooled solutions of 2a (1.0 eq., 0.1 mol L-1 in Et2O) and n-BuLi (1.1 eq., 1.6 mol L-1 in
hexanes) were mixed and lithiation as well as TRF was accomplished in the lithiation reactor.
Subsequently, a solution of MeI (1.8 eq., 0.35 mol L-1 in Et2O) was added and methylation of
the thiolate took place in the quench-reactor. Finally, after leaving the microflow reactor, the
reaction mixture was collected in a vial containing a Na2SO3 solution to avoid isomerization
induced by atmospheric oxygen. Reaction temperature (-40 °C, -20 °C, 0 °C and room
temperature) as well as tR (5 – 60 s) in the lithiation reactor were varied in order to identify
ideal reaction conditions. Overall recovery of product, starting material and dehalogenated
starting materials was approximately 75 – 80% at room temperature and almost quantitative
beneath -20 °C. While virtually no product formation was at -40 °C observed (as expected
from kinetic data), low conversion (34% yield) towards 3a took place at tR = 60 s at -20 °C.
Notably, in both experiments only small amounts of dehalogenated by-product were formed,
while the majority of the recovered material was starting compound 2a indicating that TRF
proceeds rapidly compared to the initial lithiation in the investigated temperature regime. At
0 °C significantly increased product formation was observed for higher values of tR, while
best results were obtained at room temperature (Figure 6). Fragmentation is basically
completed after 20 s and the highest yield (73%) was found at tR = 30 s. Remarkably, no
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formation of the E-isomer was observed in any of our experiments. Variation of tR in the
quench-reactor did not significantly influence the outcome of the experiment. More detailed
results of the screening are given in Table S2 and S3 in the Supplementary Data.
Figure 6. Reaction course at room temperature and reaction times from 5 to 60 seconds.
Applying the optimized conditions, a run on a preparative scale (12 mmol, room temperature,
tR = 60 s) was conducted. After purification by column chromatography, 3a could be obtained
in 56% yield.
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3.4) Non Linear Optical Properties
Recently, we showed that replacing sulfur by selenium in ene-yne derived NLO-materials
significantly boosts the SH-efficiency. This outcome can be attributed to increased density of
delocalized electrons in the conjugated π-system and thus enhanced hyperpolarizibility.31
However, the application of selenium is accompanied by drawbacks such as the toxicity of
organo-selenium compounds and complex synthesis of the required precursors. We
therefore adopted a novel design strategy to increase the electron-density in the conjugated
π-system. By attaching electron-donating substituents to the phenyl subunit, the molecular
architecture was extended to a donor-acceptor-donor structure as depicted in Scheme 3.
Scheme 3. Synthesis of “Click”-functionalized ene-yne derivatives 5i-iii via CuAAC; i: CuSO4•5H2O, Na
ascorbate, KF; D=Electron Donor, A=Electron Acceptor.
The syntheses of 5i-iii were accomplished via CuAAC starting from 3a and the
corresponding azides 4i-iii in moderate to good yields (5i: 82%, 5ii: 34%, 5iii: 57%). A
fundamental prerequisite for SHG (second harmonic generation) is the crystallization in a
noncentrosymmetric crystal class, with the exception of 432.42 Unfortunately, 5ii43 and 5iii44
both crystallized in the centrosymmetric space group P21/c. In contrast, enantiomorphic
crystals of 5i45 (space group P21, Flack parameter 0.00(2)) were grown by slow solvent
evaporation (EtOH) > 25 °C. A second centrosymmetric polymorph of 5i46 (space group:
P21/c) was obtained by growing crystals from a saturated EtOH solution upon cooling to ~
5 °C.
The molecules in the P21 polymorph of 5i (Z’=1) crystallize in layers parallel to (001),
whereby the molecules are significantly inclined with respect to the stacking direction (Figure
7). Inside these layers, molecules related by translation along a are connected via face-to-
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face contact of benzene to triazole rings (distance of least squares planes defined by the
benzene rings of two adjacent molecules 3.519 Å).
Figure 7. The crystal structure of the P21 polymorph of 5i viewed down [010];
C, N, O and S atoms are grey, blue, red and yellow, respectively; H atoms have been omitted for clarity.
The P21/c polymorph (Z’=1) is crystallo-chemically unrelated to the P21 polymorph. The
conformations of the molecules in both polymorphs differ regarding the orientation of the
methoxy group and the molecule in the P21 polymorph is considerably more twisted: The
least squares planes defined by the non-H atoms of the benzene ring and the triazole ring
form an angle of 26.7°, while the benzene and CH=CS-CH3-fragment form an angle of 18.9°.
The analogous angles in the P21/c polymorph are 9.0° and 8.7°.
Enantiomorphic crystals of 5i were subjected to SHG measurements (Figure 8). Compared
to parent compound I (Scheme 3; R = H) 5i (R = OMe) exhibits 35-fold increased SHG-
efficiency or ~ 80-times the value of KDP (potassium dihydrogen phosphate). The nonlinear
performance of 5i is the highest reported for TRF-derived NLO chromophores so far and
underlines the efficiency of the proposed donor-acceptor-donor design.
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Figure 8. SHG spectra of 5i and reference material I; the lineshape is a replica of the emission spectrum of the
femtosecond laser used in the experiment and shows the relatively large bandwidth typical for femtosecond
lasers.
4) Conclusion
Systematic investigations on the thiophene ring-fragmentation reaction focusing on improved
selectivity as well as enhanced efficiency have been presented. The application of state of
the art inline reaction monitoring technique revealed novel insights to fragmentation on-set
temperatures and reaction kinetics. As a result, reliable synthetic procedures for lab-scale
(Na2SO3 method) as well as mid- to large-scale (flow chemistry) were established. In addition
a new design concept for ene-yne based NLO materials was developed, which strengthens
the relevance of TRF products in the field of functional organic materials.
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5) Experimental Section
5.1) Synthesis
General Procedures and Methods. All reactions were performed in oven-dried glassware.
Reagents were purchased from common commercial sources and used without prior
purification. Anhydrous solvents were prepared by filtration through drying columns. Column
chromatography was performed on silica 60 (40-63 µm) using distilled solvents as given.
Melting points were recorded on an Automated Melting Point System and are corrected.
NMR spectra were recorded at 400 MHz for 1H and 100 MHz for 13C for all target compounds
(ene-yne) and at 200 MHz for 1H and 50 MHz for 13C for intermediates. Data for 1H NMR are
reported as follows: chemical shift in parts per million (ppm) from TMS (tetramethylsilane)
with the residual solvent signal as an internal reference (CDCl3 δ = 7.26 ppm), multiplicity (s
= singlet, d = doublet, t = triplet and m = multiplet), coupling constant in Hz and integration.
13C NMR spectra are reported in ppm from TMS using the central peak of the solvent as
reference (CDCl3 δ = 77.0 ppm); multiplicity with respect to proton (deduced from APT
experiments, s = quaternary C, d = CH, t = CH2, q = CH3).
General procedure for the Halogen Dance (HD) reaction.36 To a solution of
diisopropylamine (DIPA, 1.4 eq.) in anhydrous THF under argon n-BuLi (1.2 eq.) was slowly
added at -30 to -40 °C. After 30 - 60 min the thiophene species (1, 1.0 eq.) was added in
anhydrous THF at -70 °C and the reaction stirred for 1.5 - 2 h. Subsequently, the appropriate
silyl chloride (1.2 eq.) was added as a solution in anhydrous THF and the mixture stirred at rt
overnight. The reaction was poured on water, extracted with Et2O, the organic phases were
dried over anhydrous Na2SO4 and concentrated under reduced pressure.
General procedure for the Thiophene Ring-Fragmentation (TRF) reaction. To a solution
of 2a-c (1.0 eq.) in anhydrous Et2O (~0.2 M) under argon atmosphere at -40 to -60 °C n-BuLi
(1.1 eq.) was injected dropwise. After the addition the reaction was immediately warmed to rt,
stirred for 30 min and again cooled to -40 °C. At this point the addition of first Na2SO3 (1.2
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eq.) then MeI (1.5 eq.) was accomplished and the temperature subsequently raised to rt.
After a reaction time of 20 - 60 min the mixture was poured on water, extracted with Et2O, the
combined organic layers were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification was performed by column chromatography (light
petroleum).
General procedure for CuAAC. To a suspension of 3a (1.2 eq.), azide (1.0 eq.), Na
ascorbate (0.4 eq.) and CuSO4•5H2O (0.2 eq.) in t-BuOH/H2O (1:1, ~0.4M) in a microwave
reaction vial was added KF (1.4 eq.) at room temperature. Subsequently, the reaction vial
was sealed and heated to 150 °C for 30 min in a reaction microwave. Then the reaction
mixture was poured on H2O and extracted with Et2O. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Final purification was accomplished by column chromatography.
Synthetic Details. The syntheses of 2-bromo-5-methylthiophene (1a),47 2-bromo-5-
phenylthiophene (1b),48,49 2-bromo-5-[2-(trimethylsilyl)ethynyl]-thiophene (1c),50,51 3-bromo-5-
methyl-2-(trimethylsilyl) thiophene (2a)30 , 1-azido-4-methoxybenzene (4i),52 1-azido-4-
(methylthio)benzene (4ii)52 and 4-azido-N,N-dimethylbenzenamine (4iii)52 were performed
according to published protocols.
3-Bromo-2-[(1,1-dimethylethyl)dimethylsilyl]-5-methylthiophene (2b). DIPA (5.20 g, 51.4
mmol) in anhydrous THF (150 mL), n-BuLi (18.0 mL, 45.0 mmol, 2.5 M in hexanes), 1a (6.70
g, 37.8 mmol) in anhydrous THF (20 mL), TBDMS-Cl (15.0 mL, 45.0 mmol, 3 M in anhydrous
THF) and purification by bulb-to-bulb distillation in vacuo yielded 2b (8.07 g, 73 %) as slightly
yellow oil. BP: 73 - 74 °C (0.18 mbar). 1H NMR (400 MHz, CDCl3): δ = 6.78 (s, 1H), 2.47 (s,
3H), 0.96 (s, 9H), 0.38 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.6 (s), 131.1 (d),
130.1 (s), 117.0 (s), 26.8 (q), 18.2 (s), 15.1 (q), -4.3 (q) ppm. Anal Calcd for C11H19BrSSi: C,
45.35; H, 6.57; m/z 290.02 [M]+. Found: C, 45.58; H, 6.61; MS (EI, quadrupole): m/z 290.07
[M]+.
19

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3-Bromo-2-[tris(1-methylethyl)silyl]-5-methylthiophene (2c). DIPA (1.09 g, 10.8 mmol) in
anhydrous THF (80 mL), n-BuLi (3.8 mL, 9.6 mmol, 2.5 M in hexanes), 1a (1.41 g, 8.0 mmol)
in anhydrous THF (20 mL), TIPS-Cl (1.85 g, 9.6 mmol) in anhydrous THF (15 mL) and
purification by column chromatography (light petroleum) yielded 2c (2.14 g, 80 %) as white
1
solid. MP: 48.4 - 49.5 °C. H NMR (400 MHz, CDCl3): δ = 6.79 (s, 1H), 2.48 (s, 3H), 1.55
(sept., J = 7.5 Hz, 3H), 1.13 (d, J = 7.5 Hz, 18H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.5
(s), 131.2 (d), 128.0 (s), 116.9 (s), 18.8 (q), 15.1 (q), 12.4 (d) ppm. Anal Calcd for
C14H25BrSSi: C, 50.43; H, 7.56; m/z 332.06 [M]+. Found: C, 50.64; H, 7.65; MS (EI,
quadrupole): m/z 332.06 [M]+.
3-Bromo-5-phenyl-2-(trimethylsilyl)thiophene (2d).53 DIPA (6.86 g, 67.8 mmol) in
anhydrous THF (160 mL), n-BuLi (24.1 mL, 60.2 mmol, 2.5 M in hexanes), 1b (12.0 g, 50.2
mmol) in anhydrous THF (40 mL) were mixed as described in the general procedure and
stirred for 2 h at 40 °C. After the addition of TMS-Cl (6.54 g, 60.2 mmol) in anhydrous THF
(60 mL) and purification by bulb-to-bulb distillation under reduced pressure 2d (14.76 g, 94
%) was isolated as colorless oil. BP: ~110 °C (0.05 mbar). Physical properties in agreement
with literature.53
3-Bromo-2-(trimethylsilyl)-5-[2-(trimethylsilyl)ethynyl]thiophene (2e). Alterations to the
general procedure. A precooled (-40 °C) solution of LDA (DIPA (0.49 g, 4.8 mmol), n-BuLi
(1.9 mL, 4.6 mmol, 2.4 M in hexanes, anhydrous THF (40 mL)) was added to as stirred
suspension of 1c (1.00 g, 3.9 mmol) in anhydrous THF (40 mL) at -35 °C under argon
atmosphere. After a reaction time of 30 min TMS-Cl (0.60 g, 5.6 mmol) in anhydrous THF (5
mL) was injected rapidly and the mixture warmed to rt. Standard work-up (general
procedure) and column chromatography (light petroleum) gave 2e (0.84 g, 66 %) as slightly
yellow oil. BP: ~111 °C (0.2 mbar). 1H NMR (400 MHz, CDCl3): δ = 7.17 (s, 1H), 0.38 (s, 9H),
0.23 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.6 (s), 136.7 (d), 128.3 (s), 116.1 (s),
101.3 (s), 95.9 (s), -0.3 (q), -0.9 (q) ppm. Anal Calcd for C12H19BrSSi2: C, 43.49; H, 5.78; m/z
329.99 [M]+. Found: C, 43.87; H, 5.47; MS (EI, quadrupole): m/z 329.96 [M]+.
20

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Trimethyl[(3Z)-4-(methylthio)-3-penten-1-yn-1-yl]silane 3a. Starting from 2a (2.98 g, 12.0
mmol), n-BuLi (5.3 mL, 13.2 mmol, 2.5 M in hexanes), Na2SO3 (1.81 g, 14.4 mmol) and MeI
(2.55 g, 18.0 mmol) pure Z-isomer 3a (1.90 g, 86 %) was isolated as a colorless to slightly
yellow liquid after a reaction time of 20 min at rt subsequent to the addition of the methyl-
species. Physical data is in accordance to published values.30
(1,1-Dimethylethyl)dimethyl[(3Z)-4-(methylthio)-3-penten-1-yn-1-yl]silane 3b. Starting
from 2b (583 mg, 2.0 mmol), n-BuLi (0.9 mL, 2.2 mmol, 2.5 M in hexanes), Na2SO3 (303 mg,
2.4 mmol) and MeI (426 mg, 3.0 mmol) 3b (370 mg, 82 %) was isolated as a yellow low
melting solid after a reaction time of 60 min at rt after the addition of MeI. 1H NMR (400 MHz,
CDCl3): δ = 5.43 (s, 1H), 2.36 (s, 3H), 2.07 (s, 3H), 0.97 (s, 9H), 0.13 (s, 6H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 149.4 (s), 102.9 (d), 102.3 (s), 99.5 (s), 26.1 (q), 22.3 (q), 16.6 (s),
14.0 (q), -4.5 (q) ppm. Anal Calcd for C12H22SSi: m/z 227.1284 [M + H]+. Found: MS (APCI,
TOF): m/z 227.1281 [M + H]+.
Tris(1-methylethyl)[(3Z)-4-(methylthio)-3-penten-1-yn-1-yl]silane 3c. Starting from 2c
(500 mg, 1.5 mmol), n-BuLi (0.65 mL, 1.7 mmol, 2.5 M in hexanes), Na2SO3 (227 mg, 1.8
mmol) and MeI (319 mg, 2.3 mmol) 3c (302 mg, 75 %) was isolated as colorless low melting
solid after a reaction time of 60 min at rt subsequently to the addition of the methyl-species.
1H NMR (400 MHz, CDCl3): δ = 5.46 (s, 1H), 2.36 (s, 3H), 2.08 (s, 3H), 1.10 (m, 21H) ppm.
13C NMR (100 MHz, CDCl3): δ = 149.0 (s), 103.4 (s), 103.2 (d), 97.6 (s), 22.2 (q), 18.7 (q),
14.0 (q), 11.3 (d) ppm. Anal Calcd for C15H28SSi: m/z 269.1754 [M + H]+. Found: MS (APCI,
TOF): m/z 269.1746 [M + H]+.
Trimethyl[(3Z)-4-(methylthio)-4-phenyl-3-buten-1-yn-1-yl]silane 3d. Starting from 2d (623
mg, 2.0 mmol), n-BuLi (0.9 mL, 2.2 mmol, 2.5 M in hexanes), Na2SO3 (303 mg, 2.4 mmol)
and MeI (426 mg, 3.0 mmol) 3d (397 mg, 81 %) was isolated as yellow oil after a reaction
time of 30 min at rt after the addition of MeI. 1H NMR (400 MHz, CDCl3): δ = 7.41 – 7.33 (m,
13
5H), 5.76 (s, 1H), 2.13 (s, 3H),0.26 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ = 152.6 (s),
138.2 (s), 128.7 (d), 128.5 (d), 128.0 (d), 107.5 (d), 103.2. (s), 102.2 (s), 16.1 (q), 0.0 (q)
21

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ppm. Anal Calcd for C14H18SSi: m/z 247.0971 [M + H]+. Found: MS (ESI, TOF): m/z 247.0958
[M + H]+.
[(3Z)-3-(Methylthio)-3-hexen-1,5-diyn-1,6-diyl]bis(trimethylsilane) 3e. Starting from 2e
(331 mg, 1.0 mmol), n-BuLi (0.45 mL, 1.1 mmol, 2.5 M in hexanes), Na2SO3 (151 mg, 1.2
mmol) and MeI (213 mg, 1.5 mmol) 3e (206 mg, 77 %) was obtained as slightly orange low-
melting solid after a reaction time of 30 min at rt subsequently to the addition of MeI. 1H NMR
(400 MHz, CDCl3): δ = 5.87 (s, 1H), 2.42 (s, 3H),0.22 (m, 18H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 133.9 (s), 111.3 (d), 109.1 (s), 104.1 (s), 100.9 (s), 99.4 (s), 15.7. (q), -0.1 (q), -
0.2 (q) ppm. Anal Calcd for C13H22SSi2: m/z 267.1054 [M + H]+. Found: MS (ESI, TOF): m/z
267.1045 [M + H]+.
Isomerization
procedure
towards
trimethyl[(3E)-4-(methylthio)-3-penten-1-yn-1-
yl]silane 3f. 3a (220 mg, 1.2 mmol, 1.0 eq.) was dissolved in a solution of I2 (12 µmol, 1.0
mol%) in CHCl3 (~7 mL) in NMR glass tubes and irradiated with an external light source for
20 min (IntelliRay 600, 50 % intensity) resulting in a relative E-isomer content of 86 %.
Subsequently, the mixture was diluted with CHCl3 and extracted with an aqueous Na2SO3
solution. The organic layer was dried over anhydrous Na2SO4 and the solvent removed under
reduced pressure. Column chromatography (light petroleum) yielded compound 3f (167 mg,
76 %) as slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ = 5.12 (s, 1H), 2.25 (s, 3H), 2.14 (s,
13
3H), 0.19 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ = 150.9 (s), 102.5 (s), 99.0 (d), 97.7
(s), 20.6 (q), 14.7 (q), 0.1 (q) ppm. Anal Calcd for C9H16SSi: m/z 185.0815 [M + H]+. Found:
MS (APCI, TOF): m/z 185.0810 [M + H]+.
4-[(1Z)-2-(Methylthio)-1-propen-1-yl]-1-(4-methoxyphenyl)-1H-1,2,3-triazol 5i. Starting
from 3a (1.55 g, 8.4 mmol), 4i (1.04 g, 7.0 mmol), Na ascorbate (0.56 g, 2.8 mmol),
CuSO4•5H2O (0.35 g, 1.4 mmol) and KF (0.57 g, 9.8 mmol) 5i (1.50 g, 82%) was obtained
1
after column chromatography (light petroleum/Et2O 1:1). H NMR (400 MHz, CD2Cl2): δ =
8.31 (s, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 6.61 (d, J = 1.1 Hz, 1H), 3.86
13
(s, 3H), 2.42 (s, 3H), 2.27 (d, J= 1.1 Hz, 3H) ppm. C NMR (100 MHz, CD2Cl2): δ = 160.3
22

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(s), 145.6 (s), 135.9 (s), 131.2 (s), 122.6 (d), 120.6 (d), 115.2 (d), 115.1 (d), 56.2 (q), 23.8 (q),
14.7 (q) ppm. Anal Calcd for C13H15N3OS: m/z 262.1009 [M + H]+. Found: MS (ESI, TOF):
m/z 262.1010 [M + H]+.
4-[(1Z)-2-(Methylthio)-1-propen-1-yl]-1-[(4-methylthio)phenyl)]-1H-1,2,3-triazol
5ii.
Starting from 3a (288 mg, 1.56 mmol), 4ii (215 mg, 1.30 mmol), Na ascorbate (103 mg, 0.52
mmol), CuSO4•5H2O (65 mg, 0.26 mmol) and KF (106 mg, 1.82 mmol) 5ii (121 mg, 34%)
1
was obtained after column chromatography (light petroleum/Et2O 3:2). H NMR (400 MHz,
CD2Cl2): δ = 8.35 (s, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 6.62 (s, 1H), 2.54
(s, 3H), 2.42 (s, 3H), 2.27 (s, 3H) ppm. 13C NMR (100 MHz, CD2Cl2): δ = 145.7, 140.2, 136.3,
134.8, 127.6, 121.3, 120.4, 114.9, 23.8, 16.0, 14.7 ppm. Anal Calcd for C13H15N3S2: m/z
278.0780 [M + H]+. Found: MS (ESI, TOF): m/z 278.0783 [M + H]+.
N,N-Dimethyl-4-[4-[(1Z)-2-(methylthio)-1-propen-1-yl]-1H-1,2,3-triazol-1-yl]benzenamine
5iii. Starting from 3a (288 mg, 1.56 mmol), 4iii (211 mg, 1.30 mmol), Na ascorbate (103 mg,
0.52 mmol), CuSO4•5H2O (65 mg, 0.26 mmol) and KF (106 mg, 1.82 mmol) 5iii (203 mg,
1
57%) was obtained after column chromatography (light petroleum/Et2O 3:2). H NMR (400
MHz, CD2Cl2): δ = 8.26 (s, 1H), 7.56 (d, J = 9.0 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 6.61 (s,
1H), 3.01 (s, 6H), 2.41 (s, 3H), 2.26 (s, 3H) ppm. 13C NMR (100 MHz, CD2Cl2): δ = 151.1 (s),
145.3 (s), 135.4 (s), 127.3 (s), 122.2 (d), 120.5 (d), 115.4 (d), 112.7 (d), 40.8 (q), 23.8 (q),
14.7 (q) ppm. Anal Calcd for C14H18N4S: m/z 275.1325 [M + H]+. Found: MS (ESI, TOF): m/z
275.1323 [M + H]+.
5.2) IR monitoring
The ATR-IR fibre system consisted of a ReactIRTM 15 spectrometer equipped with an MCT
(mercury cadmium telluride) detector (Mettler Toledo) connected to a DiComp Probe (Mettler
Toledo, dimensions: 6.3 mm DSub AgX DiComp, 8 inches (203 mm) wetted length with a 1.5
m total length of AgX fiberconduit, optical window: 2500 to 650 cm-1, temperature range: -80-
180 °C, pH range: 1-14, wetted materials: alloy C276, diamond, gold). Spectra were
recorded over the duration of the entire reaction at a spectral resolution of 4 cm-1, averaging
23

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76 scans yielding a temporal resolution of 30 s. The fibre probe was integrated in a double-
walled cooling reactor (~10 mL volume) via feed-trough equipped with an argon inlet and a
septum. The reaction vessel was charged with anhydrous solvent (Et2O) and cooled by
cryostat (Julabo) to -60 °C. After a steady temperature in the reactor was reached the
background spectrum was recorded, the measurement started and the lithium species
added. Subsequently the respective reactant was rapidly added via a syringe (concentrations
and equivalents identical to the preparative experiments).
5.3) Flow chemistry
Screening experiments in the flow were carried out using three New Era NE-1000 syringe
pumps. 2a (4.98 g, 20.0 mmol) and n-dodecane (1.25 g) were dissolved in anhydrous Et2O
(200 mL) and a 50 mL (60 mL) syringe was filled with the solution. Methyl iodide (4.82 g,
33.9 mmol) was dissolved in anhydrous Et2O (100 mL) and a 20 mL (24 mL) syringe was
filled with the solution. A 10 mL syringe was filled with n-butyllithium (1.6 mol/L in hexanes).
Na2SO3 (3.16 g, 25 mmol) was dissolved in deionized water (100 mL) and sixteen screw-cap
vials were charged with Na2SO3 solution (1.35 mL each). The syringes were connected to the
reactor inlets via Luer-Slip adapters as follows: starting material to inlet 1; n-butyllithium to
inlet 2 and MeI to inlet 3. The chip reactor was placed on the FlowChiller54 and the
temperature was monitored. The outlet tube was placed in a waste bottle. Then 2 mL of
every solution were pushed into the system. The desired flow rates were entered into the
pumps. After starting the pumps, the dead volume time was awaited. Then the outlet tube
was placed in the first vial and two subsequent samples were collected. Upon completion the
vial was screwed tight and shaken vigorously. In such manner four sets of experiments were
conducted at room temperature, 0°C, -20°C and -40°C. Preparation of the vials and sample
collection was conducted as described above. For GC analysis 256 µL of organic layer from
every sample were transferred to a GC vial, diluted with 744 µL ethyl acetate, and analyzed.
For the prep-scale experiment, reagents were prepared in the same way, whereas the
syringe pumps were replaced with continuous pumps (Syrris Africa) and the reaction time
was prolonged. After separation of the layers the diethyl ether was evaporated under
24

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reduced pressure. Purification of the crude product was accomplished via column
chromatography (MPLC, light petrol, then ethyl acetate), yielding 1.258 g (56%) of pure
product 3a as a yellowish oil.
5.4) X-ray diffraction
Diffraction data of single crystals of 5i (two polymorphs), 5ii and 5iii were collected on a
Bruker KAPPA APEX II diffractometer system equipped with a CCD detector at 100 K under
a dry stream of nitrogen using fine sliced ϕ- and ω-scans.55 Data were reduced using SAINT-
Plus55 and corrected for absorption using SADABS55. The structures were solved with
charge-flipping implemented in SUPERFLIP56 and refined against F using Jana200657. All
non-H atoms were refined with anisotropic atomic displacement parameters. H atoms were
located in difference Fourier maps and refined freely in 5i (both polymorphs) and 5iii. In 5ii
the H atoms were placed at calculated positions and refined as riding on the parent C atom.
5.5) Second harmonic generation
The second order nonlinear optical properties of the substances were screened with second
harmonic measurements from powder samples, produced by grinding the sample crystals
with a mortar to a particle size below < 1 µm. A relative measurement of the nonlinear optical
coefficients is possible with this technique since the SH efficiency scales quadratically with
the nonlinear coefficient in this particle size regime.58 The powder samples, sandwiched
between microscope slides, were irradiated with the output of an ultrafast Yb:KGW-Laser
(Light Conversion, pulse duration 70 femtoseconds, average power 600 mW, repetition rate
75 MHz, wavelength 1034 nm), moderately focused with a 100 mm focusing lens. The
diffusely reflected SH-radiation was collected with a NA = 0.1 lens, separated from
fundamental radiation with a color filter, and spectrally analyzed with a 0.25 m grating
monochromator and a photomultiplier detector. The sample plane was positioned somewhat
out of the focal plane (towards the lens) so as to prevent any damage to the sample. After
each measurement, the samples were carefully checked for the absence of damage or
thermal modification.
25

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Acknowledgment
This work was supported in part by the Vienna University of Technology research funds and
the Austrian Federal Ministry of Science, Research and Economy. The authors acknowledge
M. Lunzer, D. Wurm, D. Koch, B. Pokorny, D. Möstl, F. Krenn and A. Kempf for supporting
the synthetic experiments. The authors also thank W. Skranc for preliminary work on this
topic. N. Jankowski is acknowledged for conducting the ion chromatography and E.
Rosenberg for performing the high resolution mass spectrometry (HRMS). The X-ray centre
of the Vienna University of Technology is acknowledged for providing access to the single-
crystal diffractometer.
26

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43. (5ii): C13H15N3S2, Mr = 277.4, monoclinic, P21/c, a = 12.1159(4) Å, b = 14.6389(9) Å, c =
7.6543(7) Å, β = 107.959(4))°, V = 1291.44(15) Å3, Z = 4, µ = 0.397 mm-1, T = 100 K, 15795
measured, 2924 independent and 1738 observed [I > 3σ(I)] reflections, 164 parameters, wR (all
data) = 0.0658, R [I > 3σ(I)] = 0.0509; CCDC reference number 1453300.
44. (5iii): C14H18N4S, Mr = 274.4, monoclinic, P21/c, a = 11.0084(2) Å, b = 8.08390(10) Å, c =
15.7948(3) Å, β = 105.7583(8)°, V = 1352.76(4) Å3, Z = 4, µ = 0.231 mm-1, T = 100 K, 53619
measured, 4901 independent and 3986 observed [I > 3σ(I)] reflections, 244 parameters, wR (all
data) = 0.0454, R [I > 3σ(I)] = 0.0345; CCDC reference number 1453301.
45. (5i), polymorph I: C13H15N3OS, Mr = 261.3, monoclinic, P21, a = 4.6978(3) Å, b = 11.8173(8) Å, c
= 11.4978(8) Å, β = 94.974(3)°, V = 635.90(7) Å3, Z = 2, µ = 0.246 mm-1, T = 100 K, 39787
measured, 7967 independent and 7364 observed [I > 3σ(I)] reflections, 223 parameters, wR (all
data) = 0.0288, R [I > 3σ(I)] = 0.0252, Flack parameter 0.00(2); CCDC reference number
1453298.
46. (5i), polymorph II: C13H15N3OS, Mr = 261.3, monoclinic, P21/c, a = 12.5889(5) Å, b = 9.1066(4) Å,
c = 11.0679(5) Å, β = 94.6707(16)°, V = 1264.63(9) Å3, Z = 4, µ = 0.247 mm-1, T = 100 K, 53752
measured, 4634 independent and 4163 observed [I > 3σ(I)] reflections, 223 parameters, wR (all
data) = 0.0493, R [I > 3σ(I)] = 0.0300; CCDC reference number 1453299.
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