Synthesis of a 2,2'-bipyridyl functionalized oligovinylene-phenylene using heck and horner-wadsworth-emmons reactions and x-ray crystal structure of e-(4-(4-bromostyryl)phenyl)(methyl)sulfane

Article abstract of DOI:10.3390/molecules17055724

The synthesis of a new 2,2'-bipyridyl functionalized oligovinylenephenylene (OVP-5) containing a methyl protected thiol using Heck coupling and the Horner-Wadsworth- Emmons reaction and is described. A key step involving a diisopropylcarbodiimide promoted dehydration of a stable ?-hydroxyphosphonate intermediate was identified. The structure of precursor E-(4-(4-bromostyryl) phenyl)(methyl)sulfane (1) was determined using X-ray crystallography.

Full text of DOI:10.3390/molecules17055724

Molecules 2012, 17, 5724-5732; doi:10.3390/molecules17055724
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of a 2,2'-Bipyridyl Functionalized Oligovinylene-
Phenylene Using Heck and Horner-Wadsworth-Emmons
Reactions and X-ray Crystal Structure of
E-(4-(4-Bromostyryl)phenyl)(methyl)sulfane
Orsolya Karácsony 1,†, Jeffrey R. Deschamps 2, Scott A. Trammell 2, Rafaela Nita 1 and
D. Andrew Knight 1,*
1
Chemistry Department, Florida Institute of Technology, 150 West University Boulevard,
Melbourne, FL 32901, USA; E-Mails: okaracsony2009@my.fit.edu (O.K.);
rnita2010@my.fit.edu (R.N.)
2
Center for Bio/Molecular Science and Engineering, US Naval Research Laboratory,
4555 Overlook Avenue, SW, Washington, DC 20375, USA;
E-Mails: jeff.deschamps@nrl.navy.mil (J.R.D.); scott.trammell@nrl.navy.mil (S.A.T.)
†
Current address: Chemistry Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
* Author to whom correspondence should be addressed; E-Mail: aknight@fit.edu;
Tel.: +1-321-674-8175; Fax: +1-321-674-8951.
Received: 8 March 2012; in revised form: 3 May 2012 / Accepted: 7 May 2012 /
Published: 14 May 2012
Abstract: The synthesis of a new 2,2'-bipyridyl functionalized oligovinylenephenylene
(OVP-5) containing a methyl protected thiol using Heck coupling and the Horner-Wadsworth-
Emmons reaction and is described. A key step involving a diisopropylcarbodiimide promoted
dehydration of a stable -hydroxyphosphonate intermediate was identified. The structure
of precursor E-(4-(4-bromostyryl)phenyl)(methyl)sulfane (1) was determined using X-ray
crystallography.
Keywords: oligovinylphenylene; HWE reaction; Heck coupling

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1. Introduction
Oligovinylphenylenes (OVPs) are conjugated molecules that have demonstrated application in
optoelectronics [1], molecular devices [2,3], photonics [4], liquid crystals [5] and organic dye
sensitizers [6]. Trammell and co-workers recently described a new strategy for the formation of
self-assembled monolayers of quinones derived from OVPs with thiol and 2,5-dimethoxylaryl head
groups. Attachment of the thiol functionalized OVP to a gold surface allowed the study of formal
redox potentials and reaction rates [7].
2,2'-Bipyridine ligands have been used extensively in homogeneous catalysis [8–14]. Martell and
co-workers showed early on that 2,2'-bipyridine Cu(II) complexes are among the most efficient in
hydrolyzing selected phosphorofluoridates, a class of compounds closely related to phosphate esters [15].
Since then, another group has reported comprehensively on the hydrolysis of other phosphate esters
with such complexes [16]. Recent work by Chang’s group showed that immobilized copper(II)-
bipyridine complexes were even more efficient at hydrolysis than the soluble complexes [17]. For
example, a copper-containing polymer prepared by free radical polymerization of a copper(II)-
vinylbipyridine complex with trimethylolpropane trimethacrylate (TRIM) showed significantly
enhanced hydrolysis over the free complexes [17].
We recently initiated a program to investigate copper(II)-bipyridine functionalized molecular wires
attached to gold nanoparticles with a view to the modulation of electronic and desolvation effects on
catalytic phosphodiester hydrolysis (Figure 1). We propose that the electronic withdrawing properties
of a highly fluorinated OVP ligand attached to a gold nanoparticle as shown, is likely to result
in decreased electron density of a neighboring copper(II)-bipyridine functionalized molecular wire,
in turn resulting in increased Lewis acidity of coordinated copper ion and consequent increase in
catalytic activity.
Figure 1. Electronic modulation of copper catalyzed organophosphate hydrolysis through
an OVP-thiol bridge attached to a gold nanoparticle.
Herein we report the synthesis and characterization of a 2,2'-bipyridine functionalized OVP
ligand containing a protected thiol and the X-ray crystal structure of a synthetic precursor
E-(4-(4-bromostyryl)phenyl)(methyl)sulfane.

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2. Results and Discussion
Numerous strategies are available for the construction of OVPs. Our synthetic approach to a
bipyridine functionalized molecular wire involved a sequential palladium catalyzed Heck coupling and
a modified Horner-Wadsworth-Emmons reaction, as shown in Scheme 1. The arylbromide precursor 1
was synthesized, and the yield improved, using a modification of the literature procedure [6] via the
reaction of diethyl 4-bromobenzylphosphonate with 4-(methylthiol)benzaldehyde which gave 1 as a
spectroscopically pure amorphous solid. Crystallization of a portion of 1 from dichloromethane yielded
colorless crystals which were of sufficient quality to be used directly for X-ray structure analysis.
Scheme 1. Synthesis of OVP-5.
The molecule crystallizes on a center of symmetry and therefore only half the molecule is present
in the asymmetric unit. Because of this, the bromine atom and the CH3S-group are present at
half-occupancy. The ORTEP representation of 1 is shown in Figure 2. X-ray analysis confirms the
E-stereochemistry previously suggested from the 1H-NMR spectrum [6].
A palladium catalyzed Heck reaction with Pd2(dba)3·CHCl3/PtBu3/NEt3 in dioxane was used to
couple 1 with 4-vinylbenzylphosphonate (2) using conditions that are expected to give a high E/Z
stereochemical ratio (Scheme 1) [18]. The OVP phosphonate OVP-3 was isolated from the reaction
mixture following silica gel flash column chromatography as a yellow solid in 70% yield and
identified using 1H-NMR spectroscopy and mass spectrometry.

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Figure 2. ORTEP style representation of 1 (displacement ellipsoids are shown at the 50% level).
Only the E-isomer was observed based on the presence of the characteristic AB pattern with
coupling constants ~16.0 Hz. Both compound 1 and 4-vinylbenzylphosphonate are recovered from the
reaction mixture with no other species being identified. Modifications of the palladium catalyzed
coupling reaction were then examined in an attempt to improve the yield of OVP-3, including a
ligand-free Heck reaction with dimethylglycine as a promoter [19], the use of Pd(OAc)2 with
Buchwald’s ligand, MePhos (2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl) [20], and
decreasing the mol% of palladium catalyst. In each case, no product OVP-3 was observed.
Reaction of the benzylphosphonate OVP-3 with 2,2'-bipyridine-5-carbaldehyde 4 under Horner-
Wadsworth-Emmons conditions with an excess of potassium t-butoxide followed by dehydration of
the -hydroxyphosphonate intermediate 6 (Schemes 1 and 2) with diisopropylcarbodiimide (DIC) gave
1
OVP-5. Evidence for 6 was provided by in situ H-NMR spectroscopy and the intermediate was not
further purified.
The phosphonic acid ethyl ester protons of 6 resonate at 1.41 and 4.01 ppm for the methyl and
methylene protons respectively with associated coupling to the phosphorus nucleus. These values are
typical for those previously reported for -hydroxyphosphonic acid diethyl esters. We have tentatively
assigned a multiplet and doublet (JHP = 28 Hz) at 5.37 and 2.91 ppm to single protons alpha to the –OH
and –PO3Et2 groups respectively. The formation of a stable, isolable -hydroxyphosphonate
intermediate in the HWE reaction is not entirely unexpected, as a carbanion-stabilizing group in the
-position is a requirement for elimination of phosphate from intermediate 8 and formation of
an alkene. Compound 6 does not possess a withdrawing group in the -position and cannot
undergo elimination.
Reichwein and Pagenkopf recently reported the saponification of -hydroxyphosphonic acid
dimethyl esters followed by diisopropylcarbodiimide (DIC) dehydration to give the corresponding
olefins [21]. We have discovered that the one-pot reaction of the phosphonic acid diethyl ester OVP-3
with an excess of potassium t-butoxide directly followed by dehydration with DIC in CHCl3 resulted
in conversion to the desired 2,2'-bipyridyl functionalized oligovinylphenylene OVP-5 via intermediate
6 (Scheme 2). We tentatively suggest that excess t-butoxide anion is responsible for monodealkylation
of the phosphonic acid ester OVP-3 [2] to give 6 which then undergoes dehydration with the
carbodiimide. Compound OVP-5 was identified with 1H-NMR spectroscopy and ESI mass
spectrometry. In situ 1H-NMR analysis of the DIC dehydration reaction shows complete disappearance
of hydrogen atoms  to both hydroxy and phosphonate groups.

Molecules 2012, 17
Scheme 2. Formation of bipyridyl-functionalized OVP-5 from -hydroxyphosphonate 6.
5728
3. Experimental
3.1. General
All reactions were conducted under N2 using standard Schlenk line and catheter-tubing techniques
1
31
13
unless otherwise stated. All H, P and C-NMR spectra were recorded on a Bruker 400 MHz NMR
spectrometer and referenced to internal tetramethylsilane. 31P-NMR spectra were referenced to
external H3PO4. Mass spectra were recorded on a Jeol AccuTOF JMS-T100LC mass spectrometer in
ESI or DART mode, or were performed by HT Labs, San Diego, CA, USA. Solvents were obtained as
follows and used without further purification: t-butanol, anhydrous dioxane, dimethylformamide
(Sigma-Aldrich), acetone, methanol, dichloromethane (Fisher), and CDCl3, (Cambridge Isotope
Laboratories). Silica gel (60–230 mesh, Sigma-Aldrich) and anhydrous MgSO4 (Fisher) were used as
received. Flash chromatography was performed using silica gel (60–230 mesh, 60Å). TLC was

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performed on SiO2 plates with fluorescent indicator. Compounds were visualized under UV light
or with phosphomolybdic acid stain. Reagents were obtained as follows and used without
further
purification:
triethylamine,
diisopropylcarbodiimide,
4-methylthiobenzaldehyde,
4-vinylbenzyl-phosphonate, Pd2(dba)·CHCl3 (Sigma-Aldrich), PtBu3, potassium t-butoxide (Fisher).
Diethyl (4-bromobenzyl)phosphonate was synthesized according to the literature procedure [6].
3.2. Synthesis of Compounds 1, OVP-3 and OVP-5
E-(4-(4-bromostyryl)phenyl)(methyl)sulfane (1). A round bottom flask was charged with diethyl
(4-bromobenzyl)phosphonate (10.0 g, 0.0325 mol) and a solution of t-BuOK (3.65 g, 0.0329 mol) in
t-BuOH (40 mL) was slowly added with stirring. Then, a solution of 4-methylthiobenzaldehyde
(2.10 g, 0.0362 mol) in t-BuOH (80 mL) was slowly added. The reaction solution was stirred for 1.5 h
and then poured into water (525 mL). The resulting precipitate was collected via filtration, dissolved in
acetone (115 mL) and the solution added to water (115 mL) to give a yellow precipitate which was
1
collected via filtration. Crystallization from CH2Cl2 gave 1 as white crystals (7.05 g, 71%). H-NMR
(CDCl3 : 7.46 (d, 2H), 7.41 (d, 2H), 7.35 (d, 2H), 7.24 (m, 2H), 7.01 (d, 2H), 2.50 (s, 3H). 13C-NMR
(CDCl3 ): 138.3 (s, SCAr), 136.3 (s, CAr), 133.8 (s, CAr), 131.7 (s, CAr), 128.7 (s, Cvinyl), 126.9 (s, CAr),
126.6 (s, CAr), 121.2 (s, CAr), 15.7 (s, SCH3). HRMS (DART) (m/z): 306.99 (100%), 304.99 (92%),
306.00 (11%), 307.99 (8%). Anal. Calcd for C15H13BrS: C, 59.02; H, 4.29. Found: C, 59.02; H, 4.31.
OVP-3. A 50 mL Schlenk flask was charged with 4-vinylbenzylphosphonate (0.163 g, 0.679 mmol), 1
(0.207 g, 0.679 mmol), triethylamine (0.290 mL, 2.03 mmol), Pd2(dba)·CHCl3 (0.006 g, 6 mol),
PtBu3 (130 µL, 10 wt % in hexane) and anhydrous dioxane (20.0 mL). The mixture was refluxed for
20 h and the resulting solution allowed to cool to room temperature. Then, CH2Cl2 (100 mL) was
added to the residue and the solution washed with brine (3 × 100 mL). The organic layer was dried
over anhydrous MgSO4, the mixture filtered and solvent removed to give a yellow-green solid which
was purified using column chromatography (SiO2, 10 g). A yellow band was eluted with 95:5
CHCl3:MeOH. Solvent was removed via rotary evaporation to give OVP-3 as a yellow solid. Yield:
1
0.2284 g, 70%. H-NMR (CDCl3, ): 7.47 (d, 2H, J = 8.0 Hz), 7.42 (d, 4H, J = 8.0 Hz), 7.36 (d, 4H,
J = 8.0 Hz), 7.26 (d, 1H, J = 8.0 Hz), 7.24 (d, 1H, J = 8.0 Hz), 7.05 (d, 2H, J = 16.0 Hz), 6.98 (d, 2H,
J = 16.0 Hz), 4.02 (m, 4H), 3.23 (d, 2H, J = 24.0 Hz), 2.51 (s, 3H), 1.25 (m, 6H). 13C-NMR (CDCl3, ):
137.9 (s, CAr), 136.7 (s, CAr), 136.6 (s, CAr), 136.0 (s, CAr), 136.1 (s, CAr), 134.3 (s, CAr), 131.1 (s, CAr),
131.0 (s, CAr), 130.1 (s, CAr), 130.2 (s, CAr), 128.2 (s, Cvinylic), 128.1 (s, Cvinylic), 128.0 (s, Cvinylic), 127.7
(s, Cvinylic), 126.9 (s, CAr), 126.8 (s, CAr), 126.8 (s, CAr), 126.7 (s, CAr), 126.7 (s, CAr), 126.6 (s, CAr),
62.1 (d, 2JCP = 6.67 Hz, OCH2), 33.7 (d, 1JCP = 138.0, CH2P), 16.4 (d, 3JCP = 5.94 Hz, CH2CH3), 15.8
(s, SCH3). 31P-NMR (CDCl3, ): 26.7 (s). HRMS (DART) (m/z): 479.18 (100%), 480.18 (24%),
478.18 (22%), 481.19 (7%). ESI-MS (m/z): [C28H31O3PS]+ 478.
OVP-5. A 50 mL Schlenk flask was charged with a solution of 4 (18.4 mg, 0.100 mmol) and OVP-3
(23.9 mg, 0.0500 mmol) in DMF (5.5 mL). The reaction flask was placed in an ice bath, and a solution
of t-BuOK (0.0283 g, 0.257 mmol) in t-BuOH (3 mL) was slowly added with stirring. The solutions
was allowed to warm to room temperature and stirred for 19 h. Then, CH2Cl2 (20 mL) was added and
the reaction mixture was washed with water (4 × 20 mL). The organic layer was dried over MgSO4

Molecules 2012, 17
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and the solvent was evaporated to give 6 which was identified by 1H-NMR. Chloroform (0.5 mL) was
added followed by DIC (0.0114 g, 90.0 mol). The mixture was stirred for 4 h, filtered on a short
silica gel plug and the solvent removed by rotary evaporation to give OVP-5 (47.8 mg, 100%).
1H-NMR (CDCl3, ): 9.1–6.2 (aromatic/vinylic CH), 2.60 (s, 3H). ESI-MS m/z: M+ 508, [M+H]+ 509,
[M−4H]+ 504.
3.3. X-ray Analysis of 1
Formula: C15H13BrS; Mr = 305.22; crystal color and shape: colorless hexagonal plate, crystal
dimensions = 0.097 × 0.234 × 0.531 mm; crystal system: monoclinic; space group C2/c (no. 15);
a = 30.840(3) Å, b = 7.1498(7) Å, c = 5.8545(6) Å;  =  = 90°,  = 96.531°; V = 1282.5(2) Å3; Z = 4;
radiation used: Mo K = 0.71073); T = 100(2) K. For more details see cif file in the supplementary
material. CCDC 881505 contains the supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html/ (or from the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336-033; E-Mail: deposit@ccdc.cam.ac.uk).
4. Conclusions
In summary, a new 2,2'-bipyridine functionalized OVP ligand with a protected thiol has been
synthesized using a combination of Horner-Wadsworth-Emmons and palladium catalyzed Heck
coupling reactions. Coordination of the ligand to copper(II), and attachment to gold nanoparticles will
be reported in due course.
Acknowledgments
This project received support from the Defense Threat Reduction Agency-Joint Science and
Technology Office for Chemical and Biological Defense (MIPR #B102405M).
Supplementary Material
Supplementary data (X-ray analysis in cif format) associated with this article can be found at:
http://www.mdpi.com/1420-3049/17/5/5724/s1.
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