Synthesis and characterization of alanine functionalized oligo/polythiophenes

Article abstract of DOI:10.1039/c0nj00016g

The synthesis and characterization of a series of monothiophenes and terthiophenes bearing amino acids are reported. The reaction of a thiophene, substituted in position 3 by either a carboxylic acid or an acetic acid moiety, with an alanine methyl ester in the presence of hydroxybenzotriazole (HOBt) and N,N′-dicyclohexylcarbodiimide (DCC) affords several mono/terthiophene- alanine methyl esters. The latter were deprotected to form the corresponding carboxylic acids. Terthiophenes have been prepared in good yields via a Stille cross coupling reaction, using a dibromothiophene-alanine methyl ester and tri-butyl stannyl thiophene. The newly prepared monomers are very stable in air and in the presence of organic solvents. The optical and electrochemical properties of the monomers and their corresponding polymers were also examined using cyclic voltammetry and indium tin oxide (ITO) electrodes.

Full text of DOI:10.1039/c0nj00016g

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PAPER
www.rsc.org/njc | New Journal of Chemistry
Synthesis and characterization of alanine functionalized
oligo/polythiophenes
Christopher D. McTiernan and M’hamed Chahma*
Received (in Gainesville, FL, USA) 8th January 2010, Accepted 9th February 2010
First published as an Advance Article on the web 16th March 2010
DOI: 10.1039/c0nj00016g
The synthesis and characterization of a series of monothiophenes and terthiophenes bearing
amino acids are reported. The reaction of a thiophene, substituted in position 3 by either
a carboxylic acid or an acetic acid moiety, with an alanine methyl ester in the presence
0
of hydroxybenzotriazole (HOBt) and N,N -dicyclohexylcarbodiimide (DCC) affords several
mono/terthiophene-alanine methyl esters. The latter were deprotected to form the corresponding
carboxylic acids. Terthiophenes have been prepared in good yields via a Stille cross coupling
reaction, using a dibromothiophene–alanine methyl ester and tri-butyl stannyl thiophene.
The newly prepared monomers are very stable in air and in the presence of organic solvents.
The optical and electrochemical properties of the monomers and their corresponding polymers
were also examined using cyclic voltammetry and indium tin oxide (ITO) electrodes.
Introduction
the absorption properties of the polymer. Electrochemical
oxidation has also been reported to prepare chiral center
Over the past decade, polythiophenes have emerged as an
functionalized polythiophene films on the surface of platinum
29,30
electrodes.
important new category of p-conjugated polymers with applica-
tions in both optical devices and sensor materials.
1
–11
Their
Another strategy, which has been employed to immobilize
enzymes, such as glutamate oxidase (GlOx), onto electroactive
species such as polythiophenes involves the formation of an
high conductivity, stability and excellent electrochemical response
have promoted an increased interest in the synthesis of a
variety of new oligothiophenes, which bear exploitable func-
tionalities that can be readily replaced by inorganic, organic,
31
amide bond between the polymer and the enzyme. This is
usually accomplished by the reaction of the carboxylic groups
of the modified polythiophene electrodes and the amino group
of the enzyme to create an amide linkage. This strategy has
resulted in the design of an amperometric microbiosensor
1
2–18
or bioorganic moieties.
This interest has also resulted in
the exploration and development of new synthetic strategies
which allow for the tuning of the solubility, conductivity,
electroactivity and electrochromic properties of these thiophene-
32
for in vivo measurements. Other examples of the systems
1
2–18
based polymers.
For example, it has been seen that the
include reversible electroactive functionalized peptides, namely
33
Fc-Leu-Phe-OMe. In this particular example it was found
introduction of organo main group elements such as divalent
sulfur or boron into oligothiophenes yields unusually high
conductivities and photoluminescent properties in the corres-
that the oxidation potential of the Fc moiety was shifted as a
consequence of the hydrogen bonding interactions between the
amino acids and the 3-aminopyrrazole derivatives. Moreover,
a ferrocene peptide containing four amino acids (Fc-Gly-Gly-
Tyr-Arg-OH) was found to act as a competitive inhibitor to
19–24
ponding polymers.
The biomolecule functionalized oligothiophenes which have
been prepared thus far, have had either their electrochemical/
2
5
optical properties or biological activities probed. Recently,
Christopherson and co-workers reported the biological activities
of different thiophenes and furans substituted by amino acids.
Their study revealed that the amino acid functionalized mono-
mers exhibit an inhibitory effect on Gar transformylase, which
is an enzyme responsible for catalyzing the transfer of a formyl
34
papain.
2
5
group between bioorganic molecules.
Polythiophenes bearing chiral centers have also been prepared
by Nilsson et al. using FeCl as oxidizing agent. In this study
they examined the stereochemical effects of chirality on the
3
Our approach toward amino acid modified conducting
materials is to investigate the synthesis of new materials with
multiple properties: materials combining the high stability and
conductivity of polythiophenes, and biological activities of amino
acids. This strategy will help control the immobilization
process of biological molecules onto conducting and semi-
conducting surfaces, which is a key step in the design of
efficient electrochemical and biological sensors. So, various
2
6–28
polymer backbone.
They found that the absorption of
both stereoisomeric polymers was similar and that the altera-
tion of the stereochemistry of the side chain does not influence
Laurentian University, Department of Chemistry & Biochemistry,
Sudbury, ON, Canada P3E 2C6. E-mail: mchahma@laurentian.ca;
Fax: +1-705-675-4844; Tel: +1-705-675-1151 (ext. 2213)
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oligothiophenes bearing an amino acid group (I and II) will be
prepared and polymerized electrochemically to form their
corresponding polythiophenes.
were prepared by reaction of 7–8 and two equivalents of tri-
3
butyl stannyl thiophene (ThSnBu ) in toluene at 100 1C. The
conversion of the methyl esters of 3, 4, 9 and 10 to the
corresponding carboxylic acids 11–14 was done in methanol
with sodium hydroxide and hydrochloric acid. All newly
synthesized products are stable in presence of air and organic
solvents.
Moreover, the amino acid activity may be probed using the
redox properties of the conducting materials. The electrical
and optical properties will also be examined using indium tin
oxide (ITO) electrodes as well as their redox properties.
Electrochemistry
Result and discussion
The redox properties of all amino acid functionalized oligo-
thiophenes were studied using cyclic voltammetry (CV) or linear
sweep voltammetry (LSV). Table 1 summarizes the oxidation
peak potentials (irreversible systems) of the prepared monomers.
It is well known that once you increase the degree of
conjugation in thiophene monomers, the oxidation peak poten-
tial decreases due to the electronic delocalization of the p-system,
which explains the low oxidation peak potential of terthio-
Synthesis
A series of oligothiophenes substituted in position 3 with
amino acids have been prepared. The 2,5 thiophene end
positions are free to allow the chemical or electrochemical
polymerization to occur. Amino acid groups and thiophene
moieties are attached through a rigid group such as an amide
group (thiophene with n = 0) or a methylene labile group
3
6–38
(
thiophenes with n = 1).
phene monomers.
Monothiophenes with a methylene
The influence of these links on the optical and electro-
group in position 3 have lower oxidation potential because
of the electro-donating behavior of this substituent.
chemical properties of amino acid functionalized oligothiophenes
and their corresponding polythiophenes will be studied. The
amino acid selected in our study is DL-alanine. It is non-polar
and has a well established chemistry. Moreover, alanine based
enzymes participate in several biochemical reactions. The
synthetic procedure of oligothiophenes bearing DL-alanine is
summarized in Scheme 1.
Oxidative electropolymerizations of irreversible systems
were performed in ACN containing 1 M n-Bu NPF by
4
6
repeated CV cycling beyond the oxidation peak potential of
the thiophene component in each monomer (i.e. 0.720 and
+
0.650 V (vs. Fc /Fc) for 9 and 10, respectively). As an example
of the electrochemical polymerization of amino acid func-
tionalized oligothiophenes, Fig. 1 represents a 10 scan electro-
polymerization curve of 9 and 10. In the oxidation process,
the peak current increases with increasing number of scans
indicating the formation of a polymer film on the surface of
the platinum electrode.
The condensation of a 3-thiophene carboxylic acid (1) and
3
-thiophene acetic acid (2) with DL-alanine methyl ester hydro-
chloride (DL-Ala-OMe HCl) in the presence of hydroxybenzo-
0
triazole (HOBT) and N,N -dicyclohexylcarbodiimide (DCC)
at room temperature in CH
2 2
Cl yields the desired products 3
and 4, respectively, with a yield of 60–70%. Compounds 1–2
5
Electrochemical properties of the deposited polymer of both
poly(9)-Pt and poly(10)-Pt were studied in a fresh solution of
supporting electrolyte that was free of monomer. For both
polymers, the peak current depends linearly (Fig. 2) on the
scan rate indicating a surface bound species. As an example,
poly(9)-Pt and poly(10)-Pt display a broad reversible oxida-
3
were dibrominated using literature procedures with a small
modification (see Experimental section) to form compounds
5
and 6. The latter were further reacted with DL-Ala-OMe
(
in the presence of HOBT and DCC) affording products 7–8.
Via Stille cross-coupling reactions using tetrakistriphenyl-
phosphine palladium(0) as the catalyst, terthiophenes 9–10
+
tion wave with E1/2 = 0.400 and 0.350 V (vs. Fc /Fc),
Scheme 1 Synthetic route for amino acid functionalized oligothiophenes.
1
418 | New J. Chem., 2010, 34, 1417–1423
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Table 1 Electrochemical and optical properties of prepared thio-
phene monomers in ACN
+
a
Compound
lmax/nm
E
p
/V (vs. Fc /Fc) ꢁ 0.02 V
b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
241
235
236
235
246
250
240
236
347
341
239
243
347
344
2.160
1.640
2.040
1.500
1.730
1.580
1.850
1.670
0.720
0.650
1.870
1.590
0.720
0.610
b
0
1
2
3
4
a
ꢂ1
b
First scan using 0.1 V s scan rate. 1 V s as scan rate.
ꢂ1
Fig. 2 CV of poly(9)-Pt (a) and poly(10)-Pt (b) at different scan rates
and variation of current with scan rate.
have a lower oxidation potential than those with only an
amide group (poly(9) and (13)).
UV-Visible
The optical properties of oligothiophenes and their corres-
ponding polymers are associated with the length of conjuga-
tion and the electro-donating/withdrawing behavior of the
substituents. As it was expected, the absorption maximum
was red shifted for terthiophenes 9, 10, 13 and 14 in com-
3
9
parison to monothiophene compounds 1–8, 11 and 12.
The presence of a methylene or a carbonyl group on either
monothiophenes or terthiophenes has no significant effect on
the lmax
.
Polymers poly(9)-Pt and poly(10)-Pt prepared via anodic
oxidation were insoluble in commonly used organic solvents,
which makes their characterization via classical spectroscopy
techniques very difficult. On the other hand, the transparent
ITO electrode provides insights into the oxidation/reduction
states and structure of the deposited material. At the oxidation
peak potential of monomers, polymers were deposited onto
the ITO electrodes for 10–20 s. All colored polymers show
Fig. 1 A 10 scan electrochemical oxidation of 9 (a) and 10 (b) in
ꢂ1
ACN. Scan rate = 0.1 V s . WE = platinum electrode; RE = silver
wire and CE = platinum wire.
respectively. All prepared polymers are electrochemically
stable. Their doping/undoping is fully reversible and no signifi-
cant change or degradation of the electrochemical behavior
was observed after repeated CV cycling 100 times.
Table 2 Electrochemical and optical properties of polythiophenes
bearing amino acid moiety [corresponding monomer].
The electropolymerization of compounds 3, 4, 11 and 12
was unsuccessful. Although the current increases during the
CV cycling, no film was deposited on the surface of the
electrode. The solubility or the instability of the produced
radical cations of the monomers or the dimers may be the
origin of this behaviour. However, 4 and 12 were polymerized
l
max
undoped/nm
l
max
doped/nm
E1/2/V
+
(vs. Fc /Fc)
Poly(9)-Pt
Poly(10)-Pt
Poly(13)-Pt
Poly(14)-Pt
484 [347]
430 [341]
474 [347]
442 [344]
633
627
633
656
0.400
0.350
0.430
0.300
chemically using NOBF as oxidation agent. As it was expected,
4
polythiophenes with a methylene group (poly(10), and (14))
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similar UV-visible behavior (Table 2). They are dark blue in
their oxidized state and yellow in their reduced state.
performed using a controlled potential in a cell with one
2
compartment using a platinum plate (1.5 cm ) and ITO
electrode as the cathode and anode, respectively.
Summary
General synthesis of 3, 4, 7 and 8
We have described the synthesis of a variety of mono/
oligothiophenes bearing amino acids that are both stable in
air and organic solvents. The UV/Vis studies of the mono/
oligothiophenes showed that the methylene linker has no
significant effect on the lmax, whereas the increased conjuga-
tion length in the terthiophenes results in a red shift. As
expected, the electrochemical studies of the monomers show
that the terthiophene monomers and monomers possessing a
methylene group exhibit lower oxidation potentials. The electro-
chemical oxidation of all terthiophenes successfully yields
several polythiophenes bearing chiral centers (amino acids),
which display excellent stability in both states (doped and
undoped). Their redox potential is low and follows the same
tendency as oligothiophene monomers. All deposited polymers
exhibit similar optical properties in both states. The synthesis
and characterization of new oligo/polythiophenes containing
specific chiral centers, L- or D-alanine, are underway. These
molecules will be immobilized on solid surfaces and will
provide chiral electrodes that will induce electrochemical or
biological responses. This concept will be extended to other
amino acids such as leucine and glycine.
DL-Alanine methyl ester hydrochloride (0.417 g, 3 mmol) and
triethylamine (0.42 mL, 3 mmol) were added to 40 mL of
anhydrous dichloromethane. After stirring for 1 h, this solution
was added dropwise to a solution of 2,5-dibromothiophene
carboxylic acid (0.858 g, 3 mmol), hydroxybenzotriazole
(0.405 g, 3 mmol), and dicyclohexylcarbodiimide (0.615 g,
3 mmol) in 60 mL of anhydrous dichloromethane that had
also been stirred for 1 h. The reaction was followed by TLC
and was found to be complete after 24 h. After filtration to
eliminate the dicyclohexylurea byproduct, the organic reaction
mixture was washed 5 times with 100 mL of a NaHCO
saturated solution followed by 5 ꢃ 100 mL washes with water.
The organic phase was then dried over MgSO and evaporated
3
4
to dryness. The product was then purified via column chromato-
graphy on silica gel with a specific eluent.
General synthesis of 9 and 10
2
,5-Dibromo-thiophene-3-carbonyl-alanine methyl ester (0.5563 g,
.5 mmol), 2-tributyl-stannyl-thiophene (1.02 mL, 3.2 mmol),
and Pd(Ph ) (0.200 g, 0.17 mmol) were added to 25 mL of
1
3
4
˚
toluene, which had been dried over 4 A molecular sieves and
degassed for 1 h with N . The reaction mixture was stirred for
2
48 h at 90 1C. The reaction was followed by TLC. Once
complete the reaction mixture was filtered through celite to
Experimental section
Generalities
remove the catalyst. The mixture was then washed 5 times with
1
00 mL of a caesium fluoride solution, followed by 5 ꢃ 100 mL
washes with water. The organic phase was then dried over
MgSO and evaporated to dryness. The crude product was
Unless stated otherwise, all reactions and manipulations were
carried out under an oxygenated atmosphere using standard
Schlenk techniques. Glassware was oven-dried at 100 1C for
4
then purified via column chromatography utilizing a solvent
system of 30% ethyl acetate and 70% dichloromethane. The
pure product was obtained as a white solid. The product was
purified via column chromatography using a solvent system of
2
4 h prior to use. Solvents were dried using activated (24 h at
˚
100 1C) molecular sieves (4 A). All reagents were purchased
from commercial sources and used as received except where
stated otherwise.
3
0% ethyl acetate and 70% dichloromethane.
1
13
H-proton ( C-carbon) NMR spectra were recorded on a
00 (50) MHz Varian NMR spectrometer. The NMR samples
were prepared by using B20 mg of product dissolved in 1 mL
of deuterated solvent (DMSO-d or CDCl ). Melting points
2
General synthesis of 11–14
Terthiophene-3-alanine methyl ester (0.134 g, 0.343 mmol)
and 1 N NaOH (2.2 mL) were added to 2 mL of methanol.
The reaction mixture was then stirred at room temperature for
6
3
are uncorrected. IR spectra were recorded on a Michelson
BOMEM Fourier-transform infrared spectrophotometer. The
KBr pellet method was utilized to obtain all spectra with a
ratio of (product : KBr) = 1 : 100. UV-Vis spectra were
recorded on an Ultropec 2100 pro spectrophotometer.
3
.5 h, after which 1 N HCl (1 mL) was added. The MeOH was
then removed in vacuo and the remaining solution was cooled
in an ice bath. 1 N HCl (2 mL) was then added dropwise to the
solution, which was then allowed to cool in the fridge over-
night. The desired product was then filtered off and dried
under reduced pressure.
The electrochemical experiments were performed using a
mAutolab type III (Ecochemie) potentiostat at room tempera-
ture (22 ꢁ 2 1C). Voltammetric measurements were performed
4 6
in acetonitrile (ACN) containing 1 M of n-Bu NPF . The
Synthesis of 2-[(thiophene-3-carbonyl)-amino]-propionic acid
methyl (3)
platinum electrode (diameter 1.6 mm) was used as the working
electrode. Platinum wire was used as auxiliary electrode and
silver wire was used as reference electrode. All oxidation peak
potentials/oxidation potentials were reported versus an internal
The product is a yellow-white solid. The solvent used for the
column chromatography on silica gel was ethyl acetate–
1
CH
0
reference ferrocene/ferrocenium redox (E = 0.390 V vs.
0
AgCl/Ag, E = 0.350 V vs. SCE). The working electrode
2
Cl
2
(20 : 90, R
F
= 0.65). Yield: 69%. Mp: 130 1C. H
NMR (200 MHz, CDCl ) d (ppm) = 1.50 (d, J = 7.0 Hz, 3H,
3
was polished on alumina before use. iR compensations were
–CH ), 3.60 (s, 3H, –COOCH ), 4.70 (m, 1H, –CH–), 6.60 (s
3
3
applied for all experiments. The bulk electrolyses were
br, 1H, –CONH–), 7.20 (m, 1H, Th-H), 7.45 (m, 1H, Th-H),
1
420 | New J. Chem., 2010, 34, 1417–1423
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1
.90 (m, 1H, Th-H). C NMR (50 MHz, CDCl
3
7
1
3
) d (ppm) =
7.6, 47.1, 51.5, 125.0, 125.4, 127.6, 135.8, 161.2, 172.3. IR
Synthesis of 2-[(2,5-dibromo-thiophene-3-carbonyl)-amino]-
propionic acid methyl ester (7)
ꢂ1
n/cm
= 1750 (CO ester), 1624 (CO amide). UV-Vis
ꢂ1
The product is a white-yellow solid. The solvent used for the
4
ꢂ1
(
CH Cl ), l
(e) = 236 nm (1.29 ꢃ 10 M cm ). HRMS
2
2
max
column chromatography on silica gel was ethyl acetate–
1
+
EI) for C H NO S [M ]: calcd. 213.0454; found 213.0463.
(
9
11
3
CH Cl
2
2
(30 : 70, R
F
= 0.74). Yield: 65%. Mp: 84 1C.
H
NMR (200 MHz, CDCl
3
) d (ppm) = 1.25 (d, J = 7.0 Hz, 3H,
CH ), 3.58 (s, 3H, –COOCH ), 4.51 (m, 1H, –CH–), 6.83 (d, J =
Synthesis of 2-(2-thiophen-3-yl-acetylamino)-propionic acid
methyl ester (4)
–
5
3
3
13
.9 Hz, 1H, –CONH–), 7.10 (s, 1H, Th-H) C NMR (50 MHz,
The product is a yellow-white solid. The solvent used for the
column chromatography on silica gel was ethyl acetate–
CDCl ) d (ppm) = 18.8, 48.8, 52.9, 112.0, 112.2, 132.1, 136.4,
3
ꢂ1
1
60.3, 173.4. IR n/cm = 1734 (CO ester) 1644 (CO amide).
1
3
ꢂ1
ꢂ1
CH Cl (20 : 90, R = 0.70). Yield: 75%. Mp: 85 1C. H
2
2
F
UV-Vis ((CH Cl ), l
(e) = 240 nm (7.84 ꢃ 10 M cm ).
2
2
max
NMR (200 MHz, CDCl ) d (ppm) = 1.40 (d, J = 7.0 Hz, 3H,
3
–
CH
3 3 2
), 3.60 (s, 3H, –COOCH ), 3.78 (s, 2H, ThCH CO), 4.60
Synthesis of 2-[2-(2,5-dibromo-thiophen-3-yl)-acetylamino]-
alanine methyl ester (8)
(
m, 1H, –CH–), 6.15 (s br, 1H, –CONH–), 7.05 (m, 1H, Th-H),
1
.19 (m, 1H, Th-H), 7.38 (m, 1H, Th-H). C NMR (50 MHz,
3
7
CDCl
3
) d (ppm) = 18.5, 38.1, 48.3, 52.7, 123.7, 126.9, 128.6,
The product is a white solid. The solvent used for the column
ꢂ1
1
34.6, 170.3, 173.5. IR n/cm
= 1750 (CO ester), 1647
chromatography on silica gel was ethyl acetate–CH
2
Cl
= 0.80). Yield: 68%. Mp: 113 1C. H NMR (200 MHz,
) d (ppm) = 1.39 (d, J = 7.0 Hz, 3H, –CH ), 3.50 (s,
2H, ThCH CO), 3.75 (s, 3H, –COOCH ), 4.58 (m, 1H, –CH–),
.17 (d, J = 5.9 Hz, 1H, –CONH–), 6.93 (s, 1H, Th-H).
2
(30 :
1
(
CO amide). UV-Vis (CH Cl
2
2
), lmax (e) = 235 nm (4.98 ꢃ
70, R
CDCl
F
3
ꢂ1
ꢂ1
+
S [M ]: calcd.
1
0 M cm ). HRMS (EI) for C10
27.0610; found 227.0613.
H
13NO
3
3
3
2
2
3
1
3
6
C
Synthesis of 2,5-dibromo-thiophene-3-carboxylic acid (5)
NMR (50 MHz, CDCl ) d (ppm) = 17.3, 35.9, 47.2, 51.5,
3
ꢂ1
1
09.7, 110.6, 130.2, 134.0, 166.9, 172.1. IR n/cm = 1756
Thiophene-3-carboxylic acid (5 g, 39 mmol) and N-bromosuccin-
0
(CO ester) 1635 (CO amide). UV-Vis (CH
ꢂ1
2
Cl
2
), lmax (e) = 236
imide (NBS) (15.1 g, 86 mmol) were added to 80 mL of N,N -
4
ꢂ1
nm (2.58 ꢃ 10 M cm ).
˚
dimethylformamide (DMF), which had been dried over 4 A
2
molecular sieves and degassed for 1 h with N . The flask was
0
0
00
0
then wrapped with aluminium foil to shield the reaction from
light. The reaction mixture was then stirred for 28 h at 50 1C.
The reaction was followed by TLC. Once the reaction had
reached completion the mixture was allowed to cool to room
temperature, after which it was washed with a saturated
solution of NaCl. Washing of the reaction mixture with NaCl
resulted in the precipitation of the desired product as a white
Synthesis of 2-[([2,2 ;5 ,2 ]-terthiophene-3 -carbonyl)-amino]-
propionic acid methyl ester (9)
The product is a white solid. The solvent used for the column
chromatography on silica gel was ethyl acetate–CH
2
Cl
= 0.74). Yield: 50%. Mp: 110 1C. H NMR (200 MHz,
CDCl ) d (ppm) = 1.59 (d, J = 7.0 Hz, 3H, –CH ), 3.93
2
(30 : 70,
1
R
F
3
3
(
s, 3H, –COOCH ), 4.90 (m, 1H, –CH–), 6.59 (d, J = 7.0 Hz,
3
solid. The white solid was then obtained via filtration. Yield:
1
H, –CONH–), 7.25 (m, 1H, Th-H), 7.33 (m, 1H, Th-H), 7.41
1
8
7
0%. Mp: 178 1C. H NMR (200 MHz, DMSO-d
.43 (s, 1H, Th-H), 13.35 (s, 1H, –COOH). C NMR (50 MHz,
6
) d (ppm) =
(
(
m, 1H, Th-H), 7.47 (m, 1H, Th-H), 7.58 (m, 1H, Th-H), 7.67
1
m, 1H, Th-H), 7. 68 (s, 1H, Th-H). C NMR (50 MHz,
1
3
3
DMSO-d
ꢂ1
6
) d (ppm) = 111.1, 118.4, 132.1, 133.1, 161.6. IR
CDCl
3
) d (ppm) = 18.4, 48.5, 52.7, 124.7, 125.4, 125.6, 127.9,
28.2, 128.3, 129.3, 133.1, 134.1, 135.1, 136.1, 136.9, 163.0,
n/cm
= 1693 (CO carboxylic acid). UV-Vis (CH Cl ),
2 2
1
1
3
ꢂ1
ꢂ1
lmax (e) = 246 nm (5.20 ꢃ 10 M cm ).
ꢂ1
73.2. IR n/cm
= 1755 (CO ester), 1633 (CO amide).
4
ꢂ1
ꢂ1
UV-Vis (CH max (e) = 339 nm (2.04 ꢃ 10 M cm ).
HRMS (EI) for C17
77.0215.
2
Cl
2
l
Synthesis of 3-(2,5-dibromo-thiophen-3-yl)-acetic acid (6)
+
[M ]: calcd. 377.0208; found
H15NO
3
S
3
Thiophene-3-acetic acid (5 g, 35 mmol) and N-bromosuccinimide
0
3
(NBS) (15.1 g, 86 mmol) were added to 80 mL of N,N -
˚
dimethylformamide (DMF), which had been dried over 4 A
0
0
00
0
Synthesis of 2-(2-[2,2 ;5 ,2 ]-terthiophen-3 -yl-acetylamino)-
propionic acid methyl ester (10)
molecular sieves and degassed for 1 h with N . The flask was then
2
wrapped with aluminium foil to shield the reaction from light.
The reaction mixture was then stirred for 28 h at 50 1C. The
reaction was followed by TLC. Once the reaction had reached
completion the mixture was allowed to cool to room tempera-
ture, after which it was washed with a saturated solution of
NaCl. Washing of the reaction mixture with NaCl resulted in the
precipitation of the desired product as a yellow solid. The
The product is a yellow solid. The solvent used for the column
chromatography on silica gel was ethyl acetate–CH Cl
2
2
1
(30 : 70, R
(200 MHz, CDCl
3.80 (s, 2H, ThCH
–CH–), 6.26 (d, J = 7.0 Hz, 1H, –CONH–), 7.3 (m, 7H,
F
= 0.60). Yield: 50%. Mp: 136 1C. H NMR
) d (ppm) = 1.45 (d, J = 7.0 Hz, 3H, –CH ),
CO), 3.83 (s, 3H, –COOCH ), 4.72 (m, 1H,
3
3
2
3
1
3
yellow solid was then obtained via filtration. Yield: 65%. Mp:
1
3
Th-H). C NMR (50 MHz, CDCl ) d (ppm) = 18.5, 37.3,
3
119 1C. H NMR (200 MHz, CDCl ) d (ppm) = 3.57 (s, 2H,
48.4, 52.7, 124.3, 125.1, 126.5, 126.9, 128.1, 131.4, 132.7, 134.7,
ꢂ1
ThCH CO), 6.91 (s, 1H, Th-H), 10.85 (s, 1H, –COOH).
2
136.7, 169.5, 173.3. IR n/cm
= 1753 (CO ester), 1639
1
3
C NMR (50 MHz, CDCl ) d (ppm) = 34.4, 109.7, 110.1,
(CO amide). UV-Vis (CH Cl ), l
(e) = 343 nm (2.22 ꢃ
3
ꢂ1
2
2
max
4
ꢂ1 ꢂ1
10 M cm ). HRMS (EI) for C H NO S [M ]: calcd.
18 17 3 3
+
1
32.8, 136.4, 170.6. IR n/cm = 1704 (CO carboxylic acid).
3
ꢂ1
ꢂ1
UV-Vis (CH Cl ), l
(e) = 250 nm (8.59 ꢃ 10 M cm ).
391.0365; found 391.0368.
2
2
max
This journal is ꢀc The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010 New J. Chem., 2010, 34, 1417–1423 | 1421

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2
-[(Thiophene-3-carbonyl)-amino]-propionic acid (11)
acid), 1639 (CO amide). UV-Vis (CH
ꢂ1
2
Cl
2
), lmax(e) = 339 nm
4
ꢂ1
+
(
1.19 ꢃ 10 M cm ). HRMS (EI) for C16
3 3
H13NO S [M ]:
Thiophene-3-alanine methyl ester (0.213 g, 1 mmol) and 1 N
NaOH (2.2 mL) were added to 2 mL of methanol. The
reaction mixture was then stirred at room temperature for
calcd. 363.0052; found 363.0054.
0
0
0 0
0
2
-(2-[2,2 ;5 ,2 ]Terthiophen-3 -yl-acetylamino)-propionic acid
3
.5 h, after which 1 N HCl (1 mL) was added. The MeOH was
(
14)
then removed in vacuo and the remaining solution was cooled
in an ice bath. 1 N HCl (2 mL) was then added dropwise to the
solution, which was then allowed to cool in the fridge over-
night. The desired product was then filtered off and dried
2
Terthiophene-3–CH -alanine methyl ester (0.128 g, 0.315 mmol)
and 1N NaOH (2.2 mL) were added to 2 mL of methanol. The
reaction mixture was then allowed to stir at room temperature
for 3.5 h, after which 1N HCl (1 mL) was added. The MeOH
was then removed in vacuo and the remaining solution was
cooled in an ice bath. 1N HCl (2 mL) was then added dropwise
to the solution, which was then allowed to cool in the fridge
overnight. The desired product was then filtered off and dried
under reduced pressure. The product is a yellow solid. Yield:
under reduced pressure. Product: white solid. Yield: 95%. Mp:
1
1
94 1C. H NMR (200 MHz, DMSO-d
6
): d (ppm) = 1.38 (d,
), 4.39 (m, 1H, –CH–), 7.58 (m, 2H,
Th-H), 8.19 (m, 1H, Th-H), 8.51 (d, J = 7.0 Hz, 1H,
J = 7.4 Hz, 3H, –CH
3
1
3
–
CONH–), 12.55 (s, 1H, –COOH). C NMR (50 MHz,
DMSO-d
6
): d (ppm) = 16.9, 47.8, 126.5, 126.9, 128.9, 137.2,
1
ꢂ1
95%. Mp: 144 1C. H NMR (200 MHz, DMSO-d ) d (ppm) =
6
1
61.8, 174.1. n/cm
= 1714 (CO carboxylic acid), 1635
1
3 2
.28 (d, J = 7.4 Hz, 3H, –CH ), 3.59 (s, 2H, ThCH CO), 4.25
(
CO amide). UV-Vis (CH
2
Cl
2
), lmax(e) = 243 nm (9.21 ꢃ
3
ꢂ1 ꢂ1
cm ). HRMS (EI) for C H NO S [M ]: calcd.
8 9 3
+
(m, 1H, –CH–), 7.08 (m, 2H, Th-H), 7.39 (m, 2H, Th-H), 7.41
1
1
0
M
(
m, 1H, Th-H), 7.58 (m, 2H, Th-H), 8.58 (d, J = 7.0 Hz, 1H,
99.0297; found 199.0302.
-(2-Thiophen-3-yl-acetylamino)-propionic acid (12)
1
3
–
CONH–), 12.61 (s, 1H, –COOH). C NMR (50 MHz,
): d (ppm) = 17.1, 35.5, 47.6, 124.0, 125.6, 126.6,
26.7, 127.3, 128.2, 128.3, 130.5, 133.1, 134.0, 134.2, 135.8,
2
DMSO-d
6
1
1
Thiophene-3–CH alanine methyl ester (0.227 g, 1 mmol) and
2
ꢂ1
68.9, 173.9. IR n/cm =1720 (CO carboxylic acid), 1647
(e) = 344 nm, (1.29 ꢃ
1
N NaOH (2.2 mL) were added to 2 mL of methanol. The
(
CO amide). UV-Vis (CH Cl ), l
4
2
2
max
reaction mixture was then allowed to stir at room temperature
for 3.5 h, after which 1N HCl (1 mL) was added. The MeOH
was then removed in vacuo and the remaining solution was
cooled in an ice bath. 1N HCl (2 mL) was then added dropwise
to the solution, which was then allowed to cool in the fridge
overnight. The desired product was then filtered off and dried
ꢂ1 ꢂ1
0 M cm ). HRMS (EI) for C H NO S [M ]: calcd.
17 15 3 3
+
1
3
77.0208; found 377.0210.
Acknowledgements
MC thanks the Laurentian University and the Natural Sciences
and Engineering Research Council of Canada (NSERC) for
supporting this work.
under reduced pressure. The product is a white solid. Yield:
1
9
1
3%. Mp: 169 1C. H NMR (200 MHz, DMSO-d ) d (ppm) =
6
.28 (d, J = 7.4 Hz, 3H, –CH ), 3.45 (s, 2H, ThCH CO), 4.25
3
2
(
(
(
m, 1H, –CH–), 7.02 (m, 1H, Th-H), 7.25 (m, 1H, Th-H), 7.45
1
3
m, 1H, Th-H), 8.55 (d, J = 7.0 Hz, 1H, –CONH–). C NMR
Notes and references
DMSO-d
6
) d (ppm) = 17.2, 36.6, 47.5, 121.9, 125.4, 128.6,
ꢂ1
1 A. Kraft, A. C. Grimsdale and A. B. Holmes, Angew. Chem., Int.
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1
35.9, 169.5, 174.0 IR n/cm = 1705 (CO carboxylic acid),
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3
2
Cl
2
), lmax (e) = 234 nm
ꢂ1
ꢂ1
+
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4
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then removed in vacuo and the remaining solution was cooled
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5
2 J. Roncali, Chem. Rev., 1992, 92, 711–738.
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under reduced pressure. Product: yellow solid. Yield: 94%.
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(
d, J = 7.4 Hz, 3H, –CH
3
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1
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3
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4
1
COOH). C NMR (50 MHz, DMSO-d ): d (ppm) = 16.7,
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8.1. 124.9, 125.0, 126.3, 127.8, 128.5, 133.3, 133.5, 134.2,
ꢂ1
1
8 L. Groenendaal, G. Zotti, P. H. Aubert, S. M. Waybright and
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422 | New J. Chem., 2010, 34, 1417–1423
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