Synthesis and characterization of 3-thiophene carboxamides containing a pyridine ring: structure, electrochemistry, and complexation

Inorganica Chimica Acta 358 (2005) 3711–3723 www.elsevier.com/locate/ica

Synthesis and characterization of 3-thiophene carboxamides containing a pyridine ring: structure, electrochemistry, and complexation S. Jarrett Howell, Cynthia S. Day, Ronald E. Noftle

*

Department of Chemistry, Wake Forest University, Gulley Drive, Box 7486 Salem Hall, Winston-Salem, NC 27109, USA Received 15 February 2005; received in revised form 4 May 2005; accepted 4 May 2005 Available online 23 June 2005

Abstract A series of new thiophene amides containing a pyridine ring has been synthesized and characterized. Single crystal X-ray structures have been determined for four of the new substances which show two distinct patterns of hydrogen-bonding. The crystal structure of the copper (II) complex of one of the ligands shows that the bonding is O,N in a square planar geometry with perchlorate ions in the axial positions. The new compounds do not undergo electropolymerization due to primary oxidation of the amide function but tuning of the amide group by introduction of an electron-withdrawing group on the pyridine ring allows electropolymerization to occur.
2005 Elsevier B.V. All rights reserved. Keywords: Aminomethylpyridine; Aminopyridine; Thiophene amides; Crystal structures; Conducting polymers; Electropolymerization; Electrochemistry; Thiophene ligands

1. Introduction Extensive research on p-conjugated organic polymers, such as polythiophene, polypyrrole, polyaniline and other cyclic species, as well as derivatives of these materials, has been carried out owing to the desirable properties that these substances possess, such as nonlinear optical behavior, electronic conductivity, and luminescence [1]. They have been proposed for use in a range of applications including chemical sensors, electroluminescent devices, electrocatalysts, batteries, smart windows, and memory devices [1–3]. The properties leading to these applications have been shown to be enhanced by incorporation of transition metals within the polymers, which contribute electronic, optical, and catalytic effects derived from the metal [4]. One such applica*

Corresponding author. Tel.: +1 336 758 5520; fax: +1 336 758 4656. E-mail address: [email protected] (R.E. Noftle).

0020-1693/$ - see front matter
2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ica.2005.05.008

tion involves redox-switchable hemilabile ligands [5–12] in which one functional group binds strongly to the metal and another functional group binds weakly resulting in catalytic behavior. A thiophene-carboxamide containing a pyridine ring could possibly function as such a system by complexation of the strongly binding pyridine moiety and the more weakly binding oxygen atom of the carboxamide group. Carboxamides and thiophene derivatives also have importance as pharmacological agents and as models for biochemical systems. For example, incorporation of the pharmacologically important thiophene group into a carboxamide analogue of 1 has been shown to result in pronounced anti-inflammatory activity [13]. Modification of the chain connecting the amide function to the thiophene ring could potentially confer desirable chemical and stereochemical properties. A class of carboxamido-3-arylsulfonylthiophenes has been reported to be considerably active against human

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cytomegalovirus (CMG) and varicella zoster virus (VZV) [14]. A series of tertiary thiophene amides was shown to be potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication [15]. Metal complexes of 2-substituted pyridine-carboxamides have pharmacological and biological importance as well. For example, copper (II) complexes containing the ligand, N-(2-pyridyl)-2,3,6-trimethoxybenzene-2 0 -carboxamide, have been found to act as non-peptide HIV-1 protease inhibitors [16]. Marscharak et al. [17] have studied a number of pyridyl carboxamide–iron (II/III) complexes as nitrile hydratase models. Clearly, carboxamides incorporating a thiophene group constitute an important class of compounds for applications in medicine and biochemistry. In this paper, we report the synthesis and electrochemistry of seven new ligands containing the thienyl group. Crystal structures of four solid ligands have been determined as well as the structure of the copper complex of 2, which demonstrates the ability of these ligands to complex with metal ions.

2. Results and discussion 2.1. Synthesis Compounds 1 and 2 were prepared by the reaction of an acid chloride with a primary amine. The synthesis of 3, 6, and 7 utilized a Rieke zinc reaction to form the thienylalkyl nitrile [18] which was hydrolyzed to the acid, treated with SOCl2 to give the acyl halide, and allowed to react with either 2-aminomethylpyridine or 2-aminopyridine to yield the respective products.The amide bond between 3-(3-thienyl)-acrylic acid and 2-aminomethylpyridine to produce 4 was formed in a reaction with DCC. 5 was prepared similarly to 2 above using 2-aminopyridine as the starting material. The copper complex of 2, compound 8, was crystallized from an ethanolic solution of stoichiometric quantities of copper perchlorate and 2. Scheme 1 displays the overall reaction sequences. Column chromatography was necessary in all cases, except for 8, to obtain analytically pure products; isolated yields ranged from 19% to 64%. Compounds 1–4 are stable at room temperature and are not hygroscopic; 1, 2, 4, and 6 exist as small, rectangular crystals (see crystal structures below) while 3 is an oily liquid. Analytical data were in accord with the chemical compositions. 2.2. Spectroscopy NMR data were consistent with the postulated structures and assignments were confirmed by COSY, HMQC, and HMBC spectra. Resonances for the ring protons of thiophene and pyridine are observed in a

range of 7.20–8.5 ppm. The N–H proton of the amide functional group also occurs in this range, but shifts further downfield to 9.2 ppm when the amide group is directly attached to the pyridine ring owing to the absence of the electron-donating methylene spacer group. In each case, the N–H amide proton is observed as a broad singlet in d6-acetone. In compounds 1–4, the methylene spacer group between the amide group and the pyridine ring occurs in the range of 4.40–4.62 ppm as a doublet indicating the absence of exchange of the nitrogen proton. Compound 4 contains an unsaturated 2-carbon spacer group between the thiophene ring and the amide group. The two protons occur as doublets at 6.69 and 7.62 ppm; 3J is 15.6 Hz, indicating that the orientation of the protons is trans [19]. Infrared spectroscopic data for the free amides showed the characteristic bands for N–H stretching from 3235 to 3322 cm
1, the amide I band from 1644 to 1711 cm
1, the amide II band from 1530 to 1560 cm
1, and the amide III band from 1246 to 1295 cm
1. Bands in the range of 1580–1599 cm
1 are associated with pyridine ring stretching [20]. Bands from 753 to 768 cm
1 are associated with the out-of-plane bending mode of the thiophene ring and are diagnostic of 3-substitution [21]. Upon complexation of Cu2+ by 2, the amide I band shifts drastically down in frequency from 1644 to 1606 cm
1, while the amide III band increases from 1249 to 1325 cm
1 which indicates coordination by oxygen [20,22,23]. The amide II band, which is mainly due to C–N stretching, should also increase in frequency slightly, but we observe a decrease which has been observed in some cases [22]. The pyridine ring-stretching band at 1590 cm
1 decreases to 1571 cm
1 and the pyridine deformation at 619 cm
1 increases to 624 cm
1 in accordance with coordination by the pyridine nitrogen atom [21,22,24]. This is confirmed by the X-ray crystal structure. In addition, a very strong band at 1120 cm
1 is observed for the perchlorate ion [22]. The EI mass spectrum for each of the compounds 1–7 showed a molecular ion as has been observed for a large number of amides [25]. For most of the methylaminopyridyl compounds, the primary fragmentation process involved cleavage of the amide C–N bond which was indicated by a base peak at m/z = 107 (C5H4NCH2NH+). However, compound (2) had a base peak at m/z = 92 ðC5 H4 NCH2 þ Þ and one close in intensity at m/z = 135 (C5H4NCH2NHCO+), although the peak at 107 was still observed at low intensity. Compound 1 showed a peak for the resonance stabilized C4H3SCO+ ion at m/z = 111 which has been commonly observed for thiophene 2-carboxamides [25,26] and one thiophene 3-carboxamide [25]. A peak at m/z = 97 indicated the thenylium ion ðC4 H3 SCH2 þ Þ which would be expected for 3-alkyl-substituted thiophenes, 2, 3, 5, 6, and 7. Compounds 5, 6 and 7 contained the aminopyridyl

S.J. Howell et al. / Inorganica Chimica Acta 358 (2005) 3711–3723

A

3713

O (CH2)y

(CH2)x

(CH2)xCOCl

(CH2)xCOOH

N H

a

b or c

S

N S

S

(a) SOCl 2; (b) 2 H2NCH2C5H4N/CH2Cl2; (c) 2 H2NC5H4N/CH2Cl2

where 1 x = 0, y = 1; 2 x = 1, y = 1; 5 x = 1, y = 0

B

O Br

(CH2)4COOH

(CH2)4CN

a

(CH2)4COCl

c

b

(CH2)4

(CH2)y N H

d,e,or f

N S

S

S

S

S

(a) BrZn(CH2)4CN/Ni(dppp)Cl2; (b) OH-/H2O/MeOH, H+; (c) SOCl2; (d) 2 H2NCH2C5H4N/CH2Cl2; (e) 2 H2NC5H4N/CH2Cl2; (f) H2NC5H3NNO2,TEA/MeCN C

R

where 3 y = 1, R = H; 6 y = 0, R = H; 7 y = 0, R = NO2

O COOH N H

a

N S

S

4

(a) DCC, DMAP, H2NCH2C5H4N/CH2Cl2

D

O

N H

2

N

+

[Cu(2)2](ClO4)2

Cu(ClO4) 6H2O EtOH

S

2

8

Scheme 1. Preparation of 1–7. (A) 1,2, and 5; (B) 3, 6, and 7; (C) 4; (D) 8.

group and the parent ions at m/z = 218 (base peak), 260, and 305 were observed. The base peak for 6 was at m/z = 94 ðC5 H4 NNH2 þ Þ and that for 7 was at 97 ðC4 H3 SCH2 þ Þ. Significant peaks were observed for other reasonable fragments of these species some of which were protonated. In the case of the copper complex, 8, information about the composition of the complex in methanol was obtained by direct introduction of the solution. The isotopic pattern observed at m/z 626, [M
ClO4]+, indicated the presence of copper and chlorine; other peaks were consistent with the composition [Cu(2)2](ClO4)2 which was supported by MS/MS on m/z = 626. 2.3. Crystal structures of 1, 2, 4, 6, and 8 All four ligands are hydrogen-bonded in the solid state. 1, 2, and 4 form extended chains via the NH and CO bonds on adjacent molecules which is in accord with results reported for other N2-(2-pyridylmethyl) amides [27,28]. Compound 6, in which the amide group is di-

rectly attached to the pyridine ring, can hydrogen bond via the pyridine nitrogen atom and the amide nitrogen atom to form a dimer; this type of intermolecular interaction has been observed in a number of cases [29–31]. The bond distances for the pyridylmethyl amides and the pyridyl amide are not significantly different from the bond lengths found in similar compounds containing these groups [32–35]. Fig. 1 shows the lattice structures of 1, 2, 4,and 6 with their hydrogen bonds shown as dashed lines. A summary of crystal data and structure refinements for 1, 2, 4, 6, and 8 is given in Table 1. Relevant bond and angle parameters, including hydrogen-bond contacts and angles, are listed in Table 2. In metal complexes of pyridylmethylamides, several possibilities exist. (1) Deprotonation of the amide by a base such that coordination occurs through both the amide and pyridine nitrogen atoms [36]. (2) Deprotonation of the amide nitrogen after complexation of the metal ion (particularly Pd2+) by the oxygen atom of the carboxyl group and the pyridine nitrogen atom [37]. (3) Tautomeric exchange of the amide proton with the

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˚ ) while C6–N1 is shortdistance is lengthened (+0.04 A ˚ ened (
0.04 A), C7–N1 is hardly changed, and C8–N2 and C9–N2 in the pyridine ring have both increased ˚ on average). The slightly but not significantly (0.02 A unit cell contains two complex ions and four perchlorate ions, the presence of which argues strongly for the neutral amide group since the copper complex bears a positive charge of 2. The bond distances for the donor-metal atoms are similar to those in the copper (II) complex of 4-(dimethylamino)-N-(2-aminomethylpyridyl)benzamide, Cu(DMABA-MP)2(ClO4)2 Æ 3H2O which is also O,Nbonded with a neutral amide nitrogen atom [39]. The structure of 8 is shown in Fig. 2 and the relevant bond parameters in Table 2. Two ligands (2) are N, O bound to the metal in a square planar arrangement with a bite angle of 94.7; the N2–Cu–N200 and O1–Cu–O100 angles are 180. The perchlorate anions are oriented along the axial positions. The thiophene ring is disordered in the complex and adopts one of two preferred orientations about the C1–C3 bond. The S–O trans conformer occurs to the extent of 67% while the cis occurs to the extent of 33%. The perchlorate anion is also disordered with two preferred orientations about the Cl1–O2 bond; the major (75%) is specified by oxygen atoms O3, O4, and O5 while the minor (25%) is specified by oxygen atoms O30 , O40 , and O50 . There is no intermolecular hydrogen-bonding between the molecular units. 2.4. Electrochemistry

Fig. 1. Lattice structures of 1, 2, 4, and 6 showing hydrogen-bonding between molecules.

carboxyl oxygen atom to form the complexed iminol; in this case, the ligand contains an additional donor [36]. (4) Complexation of the metal ion by the carboxyl oxygen atom and the pyridine nitrogen with the amide remaining neutral (protonated) [38]. In the copper complex reported here, coordination is through the oxygen atom of the carboxyl group and the amide remains neutral. Consistent with this interpretation, the C–O bond

Compound 1 showed an irreversible oxidation wave at a potential above 1 V versus a silver wire pseudoreference. No evidence was obtained for polymerization at either Pt or glassy carbon working electrodes using cyclic voltammetric or potential-step experiments. This result was not unexpected since the electron-withdrawing carbonyl group was directly attached to the thiophene ring. However, lengthening the chain by insertion of a methylene group, 2, or even a butylene moiety, 3, did not have the desired effect and no polymerization occurred even in other solvents such as nitrobenzene and propylene carbonate or in the presence of a catalyst (bithiophene). Koßmehl, et al. [40] have suggested that polymerization of thiophene amides is inhibited by preferential oxidation of the amide group, which for secondary amides occurs near 1.8 V [41]. In their case, the amide nitrogen atom was directly attached to a benzene ring. It has been noted that N-acyliminium ion formation can occur in the case of 2-methylpyridylamides by oxidation of an a-methylene group [41] which is present in four of these compounds. Such a species is very reactive and could conceivably attack the 2-position of the thiophene ring in the case of longer chain substituents. It has also been reported that oxidation of the methylene group to the carbonyl function in the ligand

S.J. Howell et al. / Inorganica Chimica Acta 358 (2005) 3711–3723

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Table 1 Summary of crystal data and structure refinements for N-(2-pyridylmethyl)-3-thienyl-carboxamide (1), N-(2-pyridylmethyl)-3-thenyl-carboxamide (2), N-(2-pyridylmethyl)-trans-3-(3-thienyl)-acrylamide (4), N-(2-pyridyl)-5-(3-thienyl)-pentyl carboxamide (6), and [bis-(N-(2-pyridylmethyl)-3thenyl-carboxamido)copper(II)] perchlorate (8) Compound

1

2

4

6

8

Empirical formula Formula weight Temperature (K) Crystal system Space group Unit cell dimensions ˚) a (A ˚) b (A ˚) c (A b () ˚ )3 Volume (A Z Calculated density (g Æ cm3) Absorption coefficient (mm
1) F(000) Crystal size (mm) Theta range () Limiting indices

C11H10N2OS 209.21 228(2) orthorhombic Pbca (No. 61)

C12H12N2OS 232.3 223(2) monoclinic P21/c (No. 14)

C13H12N2OS 244.31 198(2) monoclinic P21/c (No. 14)

C14H16N2OS 260.35 193(2) monoclinic P21/n (No. 14)

C24H24Cl2CuN4O10S2 727.03 213(2) monoclinic, P21/n (No. 14)

10.020(1) 9.5991(7) 21.418(2) 2060.1(4) 8 1.408 0.286 912 0.18 · 0.38 · 0.55 2.78–28.28
1 6 h 6 13,
12 6 k 6 1,
28 6 l 6 1 3298/2555 0.031 none

13.662(3) 9.173(3) 19.182(5) 102.49(2) 2347(1) 8 1.315 0.255 976 0.06 · 0.33 · 0.50 2.37–22.90
14 6 h 6 1,
1 6 k 6 10,
20 6 l 6 21 4222/3212 0.0334 none

12.303(1) 9.542(1) 10.754(1) 101.902(8) 1235.3(2) 4 1.314 0.246 512 0.05 · 0.20 · 0.45 2.72–25.35
14 6 h 6 14,
1 6 k 6 11,
1 6 l 6 12 2986/2270 0.0388 none

12.800(2) 5.3488(7) 18.704(2) 93.925(2) 1277.5(3) 4 1.354 0.243 552 0.14 · 0.26 · 0.50 2.18–28.26
16 6 h 6 14,
6 6 k 6 6,
23 6 l 6 23 7447/2854 0.0346 none

8.517(1) 9.837(1) 17.775(2) 100.36(1) 1464.9(3) 2 1.648 1.132 742 0.20 · 0.45 · 0.50 2.33–26.37
1 6 h 6 10,
12 6 k 6 1,
22 6 l 6 22 3780/2837 0.025 empirical, 0.933–1.000

2555/142 1.004

3212/299 1.024

2270/159 0.995

2854/167 1.043

2837/204 1.036

R1 = 0.0505, wR2 = 0.1065 R1 = 0.0990, wR2 = 0.1260

R1 = 0.0560, wR2 = 0.0914 R1 = 0.1182, wR2 = 0.1110

R1 = 0.0562, wR2 = 0.0948 R1 = 0.1317, wR2 = 0.1185

R1 = 0.0470, wR2 = 0.1190 R1 = 0.0537, wR2 = 0.1248

R1 = 0.0794, wR2 = 0.2147 R1 = 0.1164, wR2 = 0.2434

0.012(8) 0.393 and
0.263

0.0011(2) 0.234 and
0.221

none 0.228 and
0.203

none 0.453 and
0.338

none 0.711 and
0.495

Reflections collected/unique Rint Absorption correction, transmission range Data/parameters Goodness-of-fit on F2 Final R indices [Fo > 4r(Fo) data] [all data] Extinction coefficient ˚ 3) Largest differential peak and hole (e
/A P P R1 = ||F Po|
|Fc||/ |Fo|. P wR2 ¼ f P½wðF 2o
F 2c Þ2 = ½wðF 2o Þ2 g1=2 . Goof ¼ ½ wðF 2o
F 2c Þ2 =ðN d
N p Þ1=2 . P P Rint ¼ jF 2o
F 2o ðmeanÞj= F 2o .

N-(2-picolyl)picolinamide takes place in the presence of Fe(III) and Co(III) in air, although the parent ligand is stable in air over a considerable pH range [42]. Since all of the electrochemistry was performed under anaerobic conditions and there is no evidence for this type of oxidation in the copper complex of 2, this possibility can be excluded. Another possibility is that oxidation of the pyridine ring occurred resulting in a chemically reactive intermediate. Such oxidations have been observed at 1.4 V but at relatively low current densities [43], and a small wave fitting this description was observed in our system. A set of experiments designed to shed light on these questions was carried out. (1) N-(pyridyl) acetamide and N-(methylpyridyl)acetamide, both of which had the amide and pyridine functions but not the thiophene ring, were prepared by a literature method [44–46]. The electro-

chemistry for both was similar to that observed for 1–3 indicating that at least one of these groups was involved in the oxidation. (2) When a solution of 2 in dry electrolyte, which exhibited the electrochemistry of the compounds reported in this work, was treated with triflic acid, the current of the small peak at 1.4 V disappeared, indicating that the pyridine oxidation was suppressed and the main peak, which was much less affected, was due to another process. (3) Compound (4), which has a longer alkyl chain but a rigid alkene linkage, was synthesized. The coupling constant (15.6 Hz) for the protons on the alkene linkage indicated a trans conformation in solution as did the crystal structure for the solid. Molecular modeling indicated that this side chain was not sufficiently flexible to allow attack at the ring. However, the results of electrochemical experiments with 4 were very similar to

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Table 2 Selected bond lengths and bond angles for N-(2-pyridylmethyl)-3-thienyl-carboxamide (1), N-(2-pyridylmethyl)-3-thenyl-carboxamide (2), N-(2pyridylmethyl)-trans-3-(3-thienyl)-acrylamide (4), N-(2-pyridyl)-5-(3-thienyl)-pentyl carboxamide (6), and [bis-(N-(2-pyridylmethyl)-3-thenyl-carboxamido)copper(II)] perchlorate (8) Compound

1

2a

4

6

8

Formula

C11H10N2OS

C12H12N2OS

C13H12N2OS

C14H16N2OS

C24H24Cl2CuN4O10S2

Bond lengths Cu–O Cu–N(ring) C@O C(carbonyl)–C (sp3) N–C (sp2) N–C (sp3) N(ring)–C(link) N(ring)–C(ring) N–H

1.236(3) 1.481(3) (sp2) 1.340(3) 1.450(3) 1.335(3) 1.343(3) 0.86(3)

1.235(4); 1.241(4) 1.510(5); 1.503(5) 1.329(4); 1.327(4) 1.438(4); 1.449(4) 1.340(4); 1.336(4) 1.337(5); 1.333(5) 0.81(3);0.84(3)

1.235(4) 1.470(4) (sp2) 1.347(4) 1.450(4) 1.334(4) 1.338(4) 0.90(4)

1.339(2) 1.345(2) 0.87(2)

1.957(4) 2.007(7) 1.271(9) 1.505(8) 1.28(1) 1.466(9) 1.342(9) 1.363(9) 0.82(8)

Hydrogen bond contacts O. . .N H. . .Ob

2.886(3) 2.04(3)

2.790(4);2.893(4) 1.99(4);2.06(3)

2.922(4) 2.04(4)

3.176(2)(N. . .N) 2.30(2)

2.93(1); 3.24(4) 2.14(8); 2.45(9)

120.9(2) 121.9(2) 117.2(2) 121.9(2) 124(2) 114(2) 117.3(2)

121.9(3); 120.8(3) 121.2(3); 121.6(3) 116.9(3); 117.5(3) 116.8(4); 122.6(3) 115(3); 117(2) 122(3); 121(2) 116.8(4); 116.9(4)

123.5(3) 121.3(3) 115.2(3) 120.5(3) 121(3) 118(3) 117.1(3)

121.3(1) 123.3(2) 115.4(1) 126.5(1) 119(1); 115(1)(ring) 116.9(1)

118.2(7) 122.2(6) 119.4(7) 123.4(6) 115(5) 120(6) 117.5(7) 94.7(2) 85.3(2)

167(3)

167(3); 172(3)

168(3)

179(2) (N–H. . .N)

Bond angles C–C–O N–C–O C–C–N C–N–C C(sp2)–N–H C(sp3)–N–H C–N(ring)–C O–Cu–N O–Cu–N00 c Hydrogen bond angles N–H. . .O

1.218(2) 1.520(2) 1.372(2); 1.404(2)(ring)

161(7); 159(7)

a

Two independent molecules per asymmetric unit. For Compound 8, the acceptor oxygen atom is from the (disordered) perchlorate anion. c Atoms labeled with a double prime (00 ) are related to those labeled without a double prime by the crystallographic inversion center occupied by the Cu atom. b

Fig. 2. Crystal structure of 8.

those with 2 and 3 indicating that attack at the ring in 2 and 3 was probably not responsible for removal of the oxidized species. Intermolecular reactions are also possible and cannot be excluded. (4) Compounds 5 and 6, having the amide function directly attached to

the pyridine ring showed electrochemical results similar to those observed in 1–4, which indicated that the process occurred in thiophene-containing compounds even when formation of acyl-iminium ions was not possible. All of these data are consistent with oxidation of the amide function and not the thiophene or pyridine moieties; however, the thiophene oxidation potential is expected to be in a range similar to that of the amide group and, in the case of compounds in which the amide function was close to the thiophene ring, could have been obscured by the amide wave. The observation of shoulders on the main oxidation peaks for several of the new compounds is in accord with this hypothesis. It has been suggested, in the case of N-(4-nitrophenyl)-thiophene3-acetamide [40], that the electron-withdrawing nitro group raised the oxidation potential of the amide function above that of the thiophene ring potential such that oxidation of the thiophene ring could occur with subsequent electropolymerization. Accordingly, the compound N-(3-nitropyridyl)-thiophene-3-pentanamide (7) was synthesized and studied electrochemically. In this case, the compound polymerized in nitrobenzene

S.J. Howell et al. / Inorganica Chimica Acta 358 (2005) 3711–3723

Current/A*10

6

16 14

A

12 10 8 6 4 2 0 0.00 -2

0.50

1.00

1.50

2.00

1.50

2.00

Current/A*10

6

Potential/V 18 16 14 12 10 8 6 4 2 0 -20.00 -4

B

0.50

1.00

Potential/V 1200 1000

Current/A*10

6

C

800 600 400 200 0 -200

0.00

0.50

1.00

1.50

2.00

-400 -600

Potential/V

6

300

Current/A*10

readily at potentials beginning at 1.65 V. Upon an initial scan, the current increased rapidly until it peaked near 2.28 V; on the reverse scan, a wave corresponding only to reduction of the polymer on the electrode surface was observed. On the second scan, a wave corresponding to the oxidation of the polymer was noted. These features grew as successive scans were performed indicating that the film was sufficiently conducting such that oxidation of monomer could continue with subsequent deposition of more polymer. However, DEp for the polymer slowly increased with each successive scan indicating that the total resistance of the film was increasing as subsequent layers were deposited. There were indications that polymerization of 7 also occurred in acetonitrile but no film was electrodeposited. Chronoamperometry supported the interpretation of the cyclic voltammetric results. Current-time transients for deposition of poly-7 on a glassy carbon electrode from a nitrobenzene solution showed an initial current spike. The current fell to a minimum and then increased after which it reached a slowly declining plateau. The induction time decreased as the applied potential was increased. This behavior is typical for nucleation followed by multidimensional growth [44–46]. Typical cyclic voltammograms and potential step experiments for this system are shown in Fig. 3. In another experiment aimed at reducing the oxidation potential of the monomer, the electropolymerization of 7 was carried out by first depositing a few monolayers of poly-3-methylthiophene on an ITO electrode to provide a favorable substrate. The treatment did result in lowering the oxidation potential of the monomer by about 150 mV, but electrochemical characteristics of the poly-7 film were similar to those produced in the absence of the poly-3-methylthiophene film. For compounds 1–6, the currents are smaller than expected for a concentration of 5 · 10
3 mol dm
3 while that for 7, in which polymerization occurs, is closer to the expected value. The current decreased on the second and subsequent scans for 1–6 indicating the formation of an insulating film on the electrode. For solutions of higher concentration, it was noted that the initial peak current was lower than would be predicted based on those for 5 · 10
3 mol dm
3 solutions; we ascribe this to more extensive formation of the insulating film during the first scan. These data suggest that a different process for the major oxidation peak for 7 is involved. Scans of 8 over the same potential region were similar to those for 1–6, and the peak potential was close to that for 2. However, the current was comparable to that of 7, although no polymerization took place. The current decreased significantly in subsequent scans suggesting that an insulating film was also formed in this case. Electrochemical data for the primary oxidation peaks are presented in Table 3. A further study of the electrochemistry is in progress.

3717

D

250 200 150 100 50

d c b a

0 0.00 -50

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00

Time/sec

Fig. 3. Cyclic voltammograms: WE, glassy carbon; SE, Pt spiral; RE, Ag wire; m, 100 mV s
1; 5.0 · 10
3 mol dm
3; TBAPF6/CH3CN, 0.2 mol dm
3. (A) 2 (B) 4 (C) 7, 50 · 10
3 mol dm
3, sequential scans. Chronoamperometry: (D) 7, 50 · 10
3 mol dm
3, step potential (from 0 V) (a) 1.8 V (b) 1.9 V (c) 2.0 V (d) 2.1 V.

3. Experimental 3.1. Materials Thiophene carboxylic acid, (Matrix), thiophene acetic acid, copper (II) perchlorate, 2-aminopyridine, 2-methylaminopyridine, hexanes, ethyl acetate, DCC, silica gel, TLC plates, ethanol, methanol (HPLC grade) (Fisher Scientific), 2-amino-5-nitropyridine, 4-cyano-butylzinc bromide, electronic grade nitrobenzene (Aldrich) and

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Table 3 Electrochemical data for 1–8 Compound

Eap ðVÞ

iap ðA  106 Þ

1 2 3 4 5 6 7 8

2.290 1.998 1.835 1.675 1.875 1.945 2.330 2.020

19.20 14.40 18.80 17.53 16.50 14.00 56.00 74.60

WE, GC disc (0.07 cm2); CE, Pt spiral; RE, SCE; 5 · 10
3 mol dm
3; m = 100 mV s
1; TBAPF6/CH3CN, 0.2 mol dm
3.

deuterated solvents (Cambridge Isotopes Lab.) were obtained commercially. The preparation and purification of N-(pyridyl)acetamide and N-(methylpyridyl)acetamide were based on reported methods [36,47]. 3.2. Methods NMR spectra were obtained on Bruker Avance DPX300 (5 mm QNP probe) or DRX500 (5 mm TBI probe) FT NMR spectrometers. Proton shifts are in d relative to TMS while 13C NMR shifts are relative to deuterated solvent. Assignments of proton and carbon atoms were made by 1H–1H COSY, 1H–13C HMQC and 1H–13C HMBC. IR spectra were obtained on solids (KBr pellet) and liquids (KBr plates) using a Mattson Instruments 4020 Galaxy series II FT-IR spectrophotometer. UV–Visible spectra were recorded on 10
5– 10
4 M samples in methanol (10 mm quartz cell) employing an HP 8453 diode array spectrophotometer. EI-MS spectra at 70 eV were obtained on an HP 6850 GC coupled to an HP 5973N mass spectrometer (m/z = 40–400). The mass spectrum of 8 was obtained using an Agilent 1100 series MSD Trap-SL-00045 with an electrospray (ESI) interface. The trap was operated at ESI positive ion mode (ES+) with a capillary voltage of 3500 V, dry gas temperature of 325 C, dry gas flow of 5.00 mL/min, nebulizer at 15.00 psi, and infusion rate of 4 lL/min. Data were acquired over a range of 100–1000 m/z under normal scan resolution (13 000 m/z s
1) and were analyzed using MSD Trap Control 4.0 DATAANALYSIS Version 2.0 software. Elemental analyses were carried out by Atlantic Microlabs, Inc. Single crystal X-ray diffraction data for 1, 2, 4 and 8 were collected on a computer-controlled Bruker AXS P4 autodiffractometer using x scans. Single crystal X-ray diffraction data for 6 was collected on a Bruker SMART APEX CCD area detector system. Data for all structures was collected using graphite-monochromated ˚ )). Cell parameters Mo K
a (radiation (k = 0.71073 A for 6 were determined and refined using the SMART software [48] and raw frame data were integrated with the SAINT software package [49] using a narrow frame inte-

gration algorithm. Data for 8 were corrected for absorption effects using psi scans. Structures were solved using ‘‘Direct Methods’’ techniques with the Bruker AXS SHELXTL-PC software package [50]. The resulting structural parameters have been refined to convergence using counter-weighted full-matrix least-squares on F2 techniques and structural models which incorporated anisotropic thermal parameters for all nonhydrogen atoms. Amide hydrogen atoms were located from difference Fourier maps and refined as independent isotropic atoms. The remaining hydrogen atoms were included in the structure factor calculations as idealized atoms (assuming sp2- or sp3-hybridization of the carbon atoms) ‘‘riding’’ on their respective carbon atoms. A summary of crystal data and structure refinements for all structures is provided in Table 1 with a comparison of selected bond lengths and angles in Table 2. For compounds 1, 2, 4 and 8, the thiophene moiety is disordered with the 5-membered ring adopting one of two preferred orientations about the Cring–Csubstituent bond. As shown in Fig. 1, for compound 1, the position specified by atom S1 is occupied by a sulfur atom (S1) 81% of the time and a carbon atom (C50 and its hydrogen) 19% of the time. The position specified by atom C5 is occupied by a carbon atom (C5 and its hydrogen) 81% of the time and a sulfur atom (S10 ) 19% of the time. For 2, both of the crystallographically independent C4H3SCH2C(O)N(H)CH2C5NH4 molecules exhibit similar disorder. As a result, the positions specified by atom S1 for molecule A and B are occupied by a sulfur atom (S1) 76% of the time and a carbon atom (C50 and its hydrogen) 24% of the time for molecule A and occupied by a sulfur atom (S1) 88% of the time and a carbon atom (C50 and its hydrogen) 12% of the time for molecule B. The positions specified by atoms C5 for molecules A and B are occupied by a carbon atom (C5 and its hydrogen) 76% of the time and a sulfur atom ðS10 Þ 24% of the time for molecule A and by a carbon atom (C5 and its hydrogen) 88% of the time and a sulfur atom ðS10 Þ 12% of the time for molecule B. For 4, the position specified by atom S1 is occupied by a sulfur atom (S1) 69% of the time and a carbon atom (C50 and its hydrogen) 31% of the time. The position specified by atom C5 is occupied by a carbon atom (C5 and its hydrogen) 69% of the time and a sulfur atom ðS10 Þ 31% of the time. For 8, the position specified by atom S10 is occupied by a sulfur atom (S1) 67% of the time and a carbon atom (C50 and its hydrogen) 33% of the time. The position specified by C50 is occupied by a carbon (C5 and its hydrogen) 67% of the time and a sulfur S10 33% of the time. The ClO4
anion is disordered with two preferred orientations about the Cl1–O2 bond. The major (occupied 75% of the time) orientation is specified by oxygen atoms O3, O4 and O5; the minor orientation (occupied 25% of the time) is specified by oxygen atoms O30 , O40 and O50 .

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All calculations were performed using the SHELXTLPC interactive softwarepackage (G. Sheldrick, Bruker AXS, Madison, WI). Either a Pine model AFCBP 1 Bi-Potentiostat connected to a PC running PineChem software or an e-Daq potentiostat connected to a 401 e-Corder running e-Daq E-Chem software was employed for electrochemical experiments using a single compartment cell with a platinum disk, glassy carbon disk, or ITO (Donnely Corp.) as the working electrode. A Pt plate served as the counter electrode and a silver wire, referenced to SCE, as the reference electrode. The cell was cleaned with conc. HNO3, rinsed with deionized water and dried for 12 h at 130 C prior to use. Before each measurement, the working electrode (Pt or GC ) was polished using 1.0, 0.3 then 0.05 lm a-alumina paste (Buehler), rinsed with deionized water, dried, and treated with dry acetonitrile in an ultrasonic bath for 1 min. Freshly distilled acetonitrile (over CaH2) or nitrobenzene (electronic grade) was used as the solvent. TBAPF6 or TBAClO4 were employed as the supporting electrolyte (0.1 M). The electrolyte and sample solutions were purged with dry N2 for 10 min and a stream of dry N2 was maintained over the solutions during the experiments. Freshly recrystallized 2,2 0 -bithiophene and freshly distilled 3-methylthiophene were used for catalytic and copolymerization experiments, respectively. 3.3. Synthesis 3.3.1. N-(2-Pyridylmethyl)-3-thienyl-carboxamide (1) A solution of 3-thiophenecarboxylic acid (15.6 mmol) in CH2Cl2 (10 mL) was treated with thionyl chloride (15.6 mmol) by dropwise addition under dry nitrogen. After refluxing with stirring for 6 h at 125 C, the mixture was allowed to cool to room temperature after which the excess SOCl2 and CH2Cl2 were removed under vacuum. A solution of 2-(aminomethyl)pyridine (31.2 mmol) in toluene (15 mL) was added dropwise over 2 min. The mixture was allowed to react for 30 min and washed with a 0.1 M solution of sodium bicarbonate. The aqueous layer was extracted with Et2O, dried, and added to the dried organic layer. After rotary evaporation, a yellow oil was obtained, and crystallized from fresh Et2O solution at 0 C to give small crystals of 1 (0.9631 g, 4.41 mmol, 28.2%); m.p. 99– 101 C. Anal. Calc. for C11H10N2OS: C, 60.53; H, 4.62; N, 12.83. Found: C, 60.32; H, 4.66; N, 12.56%. 1 H NMR (500 MHz, d6-acetone): d, ppm; J, Hz. thiophene, 8.14 (1H, dd, J2–5 = 2.96, J2–4 = 1.29) H2; 7.58 (1H, dd, J4–5 = 5.06, J2–4 = 1.29) H4; 7.51 (1H, dd, J4–5 = 5.06, J2–5 = 2.97) H5. pyridine, 7.38 (1H, d, J3–4 = 7.85) H3; 7.72 (1H, td, J4–35 = 7.68, J4–6 = 1.80) H4; 7.22 (ddt, J4–5 = 7.46, J5–6 = 4.85, J CH2 –H5 ¼ 0.50) H5; 8.49 (d, J5–6 = 4.37) H6. 4.64 (2H, d, J NH–CH2 ¼ 5.86) NH–CH2; 8.14 (1H, s, NH). 13C{1H} NMR

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(500 MHz, d6-acetone): d, ppm 45.8, CH2–pyr; 122.5, C3, pyr; 123.3, C5, pyr; 127.6, C2, th; 128.0, C5, th; 129.4, C4, th; 137.4, C3, th; 137.7, C4, pyr; 150.2, C6, pyr; 160.1, C2, pyr; 170.0, C(O). IR (KBr, cm
1): 3844 m, 3323 s, 3097 m, 2919 w, 2367 w, 1638 s, 1547 s, 1417 m, 1294 s, 998 m, 827 m, 753 s, 670 m. UV: k (nm), log e; 204, 4.40 ± 0.01; 243, 4.00 ± 0.02. MS: m/z, rel. int., ion. 218, 16.8, molecular ion; 111, 37.0, C4H3SCO+; 107, 100, C5H4NCH2NH+; 92, 8.6, C5 H4 NCH2 þ ; 83, 9.1, C4H3S+. 3.3.2. N-(2-Pyridylmethyl)-3-thenyl-carboxamide (2) The acyl halide precursor was prepared from thenyl acetic acid [51] and its reaction with 2-(aminomethyl)pyridine (28.1 mmol) was carried out. The product mixture was worked up as described above. After extraction, the product was isolated by column chromatography (silica gel, ethyl acetate/methanol, 95%/5%). 2 crystallized from the column solvent mixture to give pale yellow crystals (1.1784 g, 4.41 mmol, 36.6%); m.p. 63–65 C. Anal. Calc. for C12H12N2OS: C, 62.04; H, 5.21; N, 12.06. Found: C, 62.19; H, 5.19; N, 12.04%. 1H NMR (500 MHz, d6-acetone): d, ppm, J, Hz. thiophene, 7.28 (1H, m, not resolved) H2; 7.10 (1H, dd, J4–5 = 4.93, J2–4 = 1.22) H4; 7.38 (1H, dd, J4–5 = 4.93, J2–5 = 2.98) H5. pyridine, 7.27 (1H,d, J3–4 = 7.66) H3; 7.68 (1H, td, J4–35 = 7.68, J4–6 = 1.80) H4; 7.20 (1H, ddt, J4–5 = 7.48, J5–6 = 4.83, J –CH2 –H5 ¼ 0.50) H5; 8.46 (1H, d, J5–6 = 4.47) H6. 3.63 (2H,s) th–CH2-C(O); 7.61 (1H, s, NH); 4.46 (2H, d, J NH–CH2 – ¼ 5.74) NH–CH2–pyr. 13C{1H} NMR (500 MHz, d6-acetone): d, ppm. 38.7, th–CH2-C(O); 45.7, NH–CH2–pyr; 122.4, C3, pyr; 123.2, C5, pyr; 123.5, C2, th; 126.6, C5, th; 130.0, C4, th; 137.4, C3, th; 137.7, C4, pyr; 150.2, C6, pyr; 159.7, C2, pyr; 171.1, C(O). IR (KBr, cm
1): 3844 s, 3275 s, 3086 w, 2919 w, 2374 w, 1644 s, 1560 s, 1435 m, 1337 m, 1029 m, 768 m, 619 m. UV: k (nm), log e; 239, 3.79 ± 0.002. MS: m/z, rel. int., ion. 232, 11.4, molecular ion; 135, 90.5, C5H4NCH2NHCO+; 107, 8.7, C5H4NCH2NH+; 97, 22.8, C4 H3 SCH2 þ ; 92, 100, C5 H4 NCH2 þ ; 65, 15.5, C 5 H5 þ . 3.3.3. N-(2-Pyridylmethyl)-5-(3-thienyl)-pentylcarboxamide (3) 3-Thienylpentylcarboxylic acid was prepared by a published method [18] and a portion (1.158 g, 6.29 mmol) was converted to the acyl halide by refluxing with thionyl chloride (0.500 mL) in CH2Cl2 solution (15 mL) under nitrogen for 5 h. After cooling, the volatiles were removed under vacuum to yield a light brown solid. A solution of 2-(aminomethyl)-pyridine (12.57 mmol) in toluene (15 mL) was added dropwise over 2 min to the residue cooled to 0 C and allowed to stand at this temperature for 30 min. The mixture was treated with 0.1 M NaHCO3 and extracted with ethyl acetate to

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give a yellow-orange organic layer which was dried and rotary-evaporated to a yellow oil. Column chromatography on silica gel (ethyl acetate/methanol, 95%/5%) gave 3 as a yellow oil (1.330 g, 4.85 mmol, 19.4% yield). d = 1.20 ± 0.02 g/cm3. Anal. Calc. for C15H18N2OS: C, 65.66; H, 6.61; N, 10.21. Found: C, 64.81; H, 6.45; N, 10.12%. 1H NMR (500 MHz, CDCl3): d, ppm, J, Hz. thiophene, 7.04 (1H, dd, J2–5 = 2.90, J2–4 = 1.14) H2; 6.96 (1H, dd, J4–5 = 4.91, J2–4 = 1.23) H4; 7.33 (1H, dd, J4–5 = 4.91, J2–5 = 2.95) H5. pyridine, 7.30 (1H, d, J3–4 = 7.86) H3; 7.73 (1H, td, J4–35 = 7.68, J4–6 = 1.80) H4; 7.23 (1H, ddt, J4–5 = 7.45, J5–6 = 4.87, J –CH2 –H5 ¼ 0.49) H5; 8.52 (1H, ddd, J5–6 = 4.78, J4–6 = 1.60, J3–6 = 0.87) H6. 2.63 (2H, t, J tp-CH2 CH2 ¼ 6.93) th–CH2CH2CH2CH2; 1.70 (4H, m, not resolved, 4H) th–CH2CH2CH2CH2; 2.31 (2H, t, J CH2 CH2 ¼ 7.09) th–CH2CH2CH2CH2; 7.70 (1H, s) N–H; 4.48 (2H, d, J NH–CH2 – ¼ 5.83) NH–CH2–pyr. 13C{1H} NMR (500 MHz, d6-acetone): d, ppm. 25.7, th–CH2CH2CH2CH2; 30.4, th–CH2CH2CH2CH2; 30.5, th–CH2CH2CH2CH2; 36.7, th–CH2CH2CH2CH2; 44.4, NH–CH2–pyr; 120.4, C2, th; 123.0, C5, th; 123.6, C3, pyr; 125.0, C5, pyr; 128.6, C4, th; 138.0, C4, pyr; 142.9, C3, th; 148.5, C6, pyr; 156.6, C2, pyr; 173.4, C(O). IR (KBr, cm
1): 3288 s, 3067 m, 2930 s, 2858 m, 1649 s, 1591 m, 1537 s, 1474 m, 1435 m, 1350 m, 1245 m, 1148 w, 1048 w, 995 w, 855 w, 833 m, 756 m, 685 w, 633 w, 480 w. UV: k (nm), log e; 240, 3.77 ± 0.02. MS: m/z, rel. int., ion. 274, 40.4, molecular ion; 164, 19.2, C5 H4 NCH2 NHCOC2 H5 þ ; 163, 23.1, C5 H4 NCH2 NHCOC2 H4 þ ; 150, 9.6, C5H4NCH2NHC2H3O+; 135, 10.6, C5H4NCH2NHCO+; 110, 17.3, C4 H3 SC2 H3 þ ; 109, 23.1, C4 H3 SC2 H2 þ ; 108, 17.3, C5 H4 NCH2 NH2 þ ; 107, 100, C5H4NCH2NH+; 97, 32.7 C4 H3 SCH2 þ ; 93, 35.6, C5 H4 NCH3 þ ; 92, 36.5, C5 H4 NCH2 þ ; 80, 9.6, C5H6N+ 65, 10.6 C5 H5 þ . 3.3.4. N-(2-Pyridylmethyl)-trans-3-(3-thienyl)acrylamide (4) A solution of trans-3-(3-thienyl) acrylic acid (5 mmol), 2-(aminomethyl)-pyridine (5.5 mmol), and 4-dimethylamino pyridine (0.500 mmol) in CH2Cl2 (75 mL) was held at 0 C and dicyclohexylcarbodiimide (5.5 mmol) was added with vigorous stirring after which the mixture was stirred for 4 h at 0 C and then brought to RT. A white precipitate (DCU) which formed was removed by filtration and washed with cold CH2Cl2. The CH2Cl2 solution was subjected to rotary evaporation and the residue was purified by column chromatography on silica (ethyl acetate/methanol, 95%/5%). The collected column material crystallized from ethyl acetate/ hexanes to give 4 as a white powder (0.518 g, 2.12 mmol, 42.4% yield); m.p. 90–92 C. Anal. Calc. for C13H12N2OS: C, 63.91; H, 4.95; N, 11.47. Found: C, 63.94; H, 4.92; N, 11.40%. 1H NMR (500 MHz, CDCl3): d, ppm, J, Hz. thiophene, 7.72 (1H, dd, J2–5 = 3.33, J2–4 =

1.08) H2; 7.42 (1H, dd, J4–5 = 5.06, J2–4 = 0.88) H4; 7.53 (1H, ddd, J4–5 = 5.06, J2–5 = 2.94, J H5 –CH@CH ¼ 0.58) H5. pyridine, 7.38 (1H, d, J3–4 = 7.85) H3; 7.74 (1H, td, J4–35 = 7.68, J4–6 = 1.79) H4; 7.26 (1H, ddt, J4–5 = 7.43, J5–6 = 4.87, J –CH2 –H5 ¼ 0.47) H5; 8.51 (1H, dd, J5–6 = 4.47, J = not resolved) H6. 6.70 (1H, d, JACH@CHA = 15.6) th–CH@CHAC(O); 7.62 (1H, d, JCH@CH- = 15.6) th–CH@CHAC(O); 7.81 (1H, s, NH); 4.62 (2H, d, J NH–CH2 ¼ 5.76) NH–CH2–pyr. 13C{1H} NMR (500 MHz, d6-acetone): d, ppm. 45.9, NH–CH2– pyr; 122.6, C3, pyr; 122.7, th–CH@CH–C(O); 123.3, C5, pyr; 126.5, C2, th; 128.1, C5, th; 128.2, C4, th; 134.8, th–CH@CH–C(O); 137.8, C4, pyr; 139.7, C3, th; 150.3, C6, pyr; 159.8, C2, pyr; 166.7, C(O). IR (KBr, cm
1): 3278 s, 3076 m, 2913 m, 1654 s, 1614 s, 1544 s, 1432 m, 1387 w, 1330 s, 1278 m, 1204 m, 1140 w, 1036 m, 975 m, 863 m, 768 s, 687 m, 613 w, 527 w, 458 w. UV: k (nm), log e; 207, 4.15 ± 0.01; 231, 4.09 ± 0.01; 272, 4.43 ± 0.01. MS: m/z, rel. int., ion. 244, 27.9, molecular ion; 147, 51.9, C5H4NCH2NCOCH+; 137, 51.0, C4H3SCHCHCO+; 109, 45.2, C4H3SCHCH+; 107, 100, C5H4NCH2NH+, 93, 92.3, C5 H4 NHCH2 þ ; 92, 19.2, C5 H4 NCH2 þ ; 65, 28.8, C5 H5 þ . 3.3.5. N2-(2-Pyridyl)-5-(3-thienyl)-methyl-carboxamide (5) A solution of 3-thiopheneacetic acid (5 mmol), 2aminopyridine (5.5 mmol), and 4-dimethylamino pyridine (0.5 lmol) in CH2Cl2 (75 mL) was placed in a 250 mL round bottom flask and cooled to 0 C. Dicyclohexylcarbodiimide (5.5 mmol) was added to the CH2Cl2 solution with vigorous stirring. The reaction mixture was allowed to stir for 4 h at 0 C during which time a white precipitate formed. The mixture was brought to room temperature, the white solid was removed on a filter frit, washed with cold CH2Cl2, and the filtrate was dried. After removal of the solvent by rotary evaporation, the residue was purified by column chromatography on silica (ethyl acetate/methanol, 95%/5%) to obtain a yellow solid which was recrystallized from hexane to give fine, white needles of 5 (0.258 g, 1.17 mmol, 23.3% yield); m.p. 108–109 C. Anal. Calc. for C11H10N2OS: C, 60.57; H, 4.62; N, 12.83. Found: C, 60.59; H, 4.66; N, 12.71%. 1H NMR (500 MHz, d6-acetone) d, ppm; J, Hz: thiophene, 7.38 (1H, dd, J2–5 = 2.94, J24 = 1.14) H2; 7.18 (1H, dd, J4–5 = 4.93, J2–4 = 1.22) H4; 7.44 (1H, dd, J4–5 = 4.80, J2–5 = 3.00) H5. pyridine, 8.21 (1H, d, J3–4 = 8.38) H3; 7.75 (1H, ddd, J3–4 = 8.39, J4–5 = 7.40, J4–6 = 1.85) H4; 7.06 (1H, ddd, J4–5 = 7.33, J5–6 = 4.88, J NH–H5 ¼ 1.00) H5; 8.25 (1H, ddd, J5–6 = 4.85, J4–6 = 1.84, J3–6 = 0.85) H6. 3.87 (2H, s) th–CH2–C(O); 9.40 (1H, s, NH). 13 C{1H} NMR (500 MHz, d6-acetone): d, ppm.: 39.6, th–CH2-C(O); 114.5, C3, pyr; 120.6, C5, pyr; 124.0, C2, th; 126.9, C5, th; 130.0, C4, th; 136.7, C3, th; 139.1, C4, pyr; 149.2, C6, pyr; 153.6, C2, pyr; 170.4, C(O). IR

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(KBr, cm
1): 3236 s, 3186 s, 3131 m, 3108 m, 3078 m, 3055 s, 2969 m, 2933 w, 2859 w, 2808 w, 2397 w, 2290 w, 1941 w, 1835 w, 1663 s, 1599 s, 1578 s, 1547 s, 1459 s, 1434 s, 1386 m, 1325 s, 1295 s, 1238 m, 1149 m, 1139 s, 1095 m, 1051 w, 997 w, 970 m, 930 w, 849 m, 811 m, 764 s, 737 m, 699 m, 612 s, 555 m, 508 w, 432 w, 404 w. UV: k (nm), log e: 237, 4.20 ± 0.02; 276, 3.71 ± 0.07.MS: m/z, rel. int., ion. 218, 100, molecular ion; 124, 25, C4H3SCH2CO+; 121, 15.4, C5H4NNHCO+; 97, 66.4, C4 H3 SCH2 þ ; 95, 47.1, C5 H4 NHNH2 þ ; 94, 100, C5 H4 NNH2 þ ; 78, 38.5, C5H4N+. 3.3.6. N2-(2-Pyridyl)-5-(3-thienyl)-pentyl carboxamide (6) 6 was prepared in the same manner as 3 above. 3-Bromothiophene (25 mmol) was allowed to react with 4-cyanobutylzinc bromide (25 mmol) in the presence of Ni(dppp)Cl2 catalyst (1.25 mmol) and the product was hydrolyzed to give the corresponding acid. The acid was converted to the acyl chloride using thionyl chloride and this was allowed to react with 2-aminopyridine (5.4 mmol) in CH2Cl2 following a reported procedure [51]. The workup was the same as for 3 but, in the final chromatography on silica gel, the eluant ratio was: ethyl acetate/hexanes, 50%/50%. The purified white solid was recrystallized from hexanes to give white needles of (6) (0.450 g, 1.73 mmol, 64.0% yield); m.p. 40–42 C. Anal. Calc. for C14H16N2OS: C, 64.59; H, 6.19; N, 10.76. Found: C, 64.69; H, 6.24; N, 10.82%. 1H NMR (500 MHz, CDCl3) d, ppm, J, Hz.: thiophene, 7.09 (1H,dd, J2–5 = 2.90, J2–4 = 1.16) H2; 7.00 (1H, dd, J4–5 = 4.92, J24 = 1.24) H4; 7.34 (1H, dd, J4–5 = 4.91, J25 = 2.95) H5. pyridine, 8.21 (1H, d, J3–4 = 8.40) H3; 7.72 (1H, ddd, J3–4 = 8.38, J45 = 7.34, J4–6 = 1.87) H4; 7.03 (1H, ddd, J4–5 = 7.32, J5–6 = 4.87, J NH–H5 ¼ 1.03) H5; 8.23 (1H, ddd, J5–6 = 4.85, J4–6 = 1.89, J3–6 = 0.88) H6. 2.68 (2H, t, J th–CH2 CH2 ¼ 6.90) th–CH2CH2CH2CH2; 1.72 (4H, m, not resolved) th–CH2CH2CH2CH2; 2.53 (2H, t, J CH2 CH2 –CðOÞ ¼ 7.04) th–CH2CH2CH2CH2; 9.33 (1H, s, NH). 13C{1H} NMR (500 MHz, d6-acetone): d, ppm: 26.1, th–CH2CH2CH2CH2; 30.9, th–CH2CH2CH2CH2; 31.3, th– CH2CH2CH2CH2; 37.7, th–CH2CH2CH2CH2; 114.6, C3, pyr; 120.3, C5, pyr; 121.3, C2, th; 126.5, C5, th; 129.5, C4, th; 139.0, C4, pyr; 143.9, C3, th; 149.2, C6, pyr; 153.8, C2, pyr; 173.0, C(O). IR (KBr, cm
1): 3245 m, 3220 m, 3115 m, 3032 w, 2947 m, 2916 m, 2895 m, 2855 w, 1697 s, 1580 s, 1530 s, 1462 s, 1435 s, 1419 s, 1368 m, 1313 s, 1285 s, 1200 m, 1160 s, 1080 w, 1046 w, 936 m, 831 w, 799 m, 779 s, 756 s, 739 s, 598 m, 516 m. UV: k (nm), log e: 236, 4.28 ± 0.01; 277, 3.80 ± 0.02. MS: m/z, rel. int., ion.260, 41.8, molecular ion; 150, 29.6, C5 H4 NHNHCOCH2 CH2 þ ; 149, 62.2, C5 H4 NNHCOCH2 CH2 þ ; 136, 15.3, C5 H4 NHNHCOCH2 þ ; 121, 50.0, C5H4NNHCO+; 110, 15.3, C4H3SCH2CH+; 97, 55.1, C4 H3 SCH2 þ ; 95, 26.5,

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C5 H4 NHNH2 þ ; 94, 100, C5 H4 NNH2 þ ; 78, 20.4, C5H4N+; 67, 20.4, (CH)4NH+. 3.3.7. N2-(5-Nitro-2-pyridyl)-5-(3-thienyl)-pentancarboxamide (7) 3-Thienyl-pentanoyl chloride was prepared as previously described by hydrolysis of the product of 3-bromothiophene and 1-cyanobutylzinc bromide to the acid and subsequent treatment with thionyl chloride. A solution of 2-amino-5-nitropyridine (10.9 mmol) in CH3CN (40 mL) was added dropwise over 2 min to a solution of the acyl halide (5.4 mmol) in CH3CN held at 0 C; the stirred mixture was allowed to warm to room temperature and react for 1 h after which most of the solvent was removed. The residue was extracted with CH2Cl2; the extract was washed with 0.1 M NH4Cl followed by 0.1 M NaHCO3 and finally deionized water. The organic layer was dried, evaporated to dryness and the residue separated by column chromatography using silica gel (ethyl acetate/methanol, 95%/5%) to obtain a green-yellow solid (7) (361 mg, 1.18 mmol, 22.0%). 1H NMR (500 MHz, d, ppm, DMSO-d6): thiophene, 7.18 (d, not resolved) H2; 7.02 (d, J45 = 4.84) H4; 7.47 (d, J45 = 4.83) H5. Pyridine, 8.33 (d, J34 = 9.27) H3; 8.62 (dd, J34 = 9.27, J46 = 2.81) H4; 9.19 (d, J46 = 2.83) H6. 2.65 (t, 2H, J th–CH2 CH2 ¼ 6.70) th–CH2CH2CH2CH2; 1.65 (m, 4H, not resolved) th–CH2CH2CH2CH2; 2.54 (m, 2H, not resolved, solvent peak has same chemical shift) th–CH2CH2CH2CH2; 11.23 (s, N–H). 13C{1H} NMR (75.5 MHz, d, ppm, DMSO-d6): 24.3, th– CH2CH2CH2CH2; 29.2, th–CH2CH2CH2CH2; 29.5, th–CH2CH2CH2CH2; 35.9, th–CH2CH2CH2CH2; 112.4, C3, pyr; 120.3, C2, th; 125.7, C5, th; 128.3, C4, th; 134.2, C4, pyr; 139.7, C2, pyr; 142.2, C3, th; 144.7, C6, pyr; 156.1, C5, pyr; 173.0, C(O). IR (KBr, cm
1): 3280 s, 3251 m, 3134 w, 3099 m, 2935 m, 2906 m, 2858 w, 1975 w, 1758 w, 1711 s, 1640 w, 1606 s, 1581 s, 1535 s, 1511 s, 1458 m, 1421 m, 1388 s, 1343 s, 1309 s, 1274 s, 1201 s, 1140 s, 1112 s, 1045 w, 1016 m, 942 w, 908 w, 861 m, 835 m, 798 m, 763 s, 713 m, 630 w, 594 w, 532 w, 504 w, 458 w, 420 w. MS: m/z, rel. int., ion. 305, 55.7, molecular ion; 207, 10.3, NO2 C5 H3 NNHCOC3 H5 þ ; 195 19.6, NO2 C5 H3 NH NHCOC2 H4 þ ; 194, 55.7, NO2 C5 H3 NNHCOC2 H4 þ ; 181, 20.6, NO2 C5 H3 NHNHCOCH2 þ ; 179, 12.4, NO2 C5 H3 NNHCOCH2 þ ; 166, 55.6, NO2C5H3NNHCO+; 140, 25.8, NO2 C5 H3 NHNH2 þ ; 139, 44.3, NO2 C5 H3 NNH2 þ ; 124, 39.2, C4H3SCH2CH2CH+; 123, 43.3, C4H3SCH2CHCH+; 110, 40.2, C4H3SCH2CH+; 109, 16.5, C4H3SCHCH+; 97, 100, C4 H3 SCH2 þ . 3.3.8. Bis-(N2-(2-pyridylmethyl)-3-thenyl-carboxamido) copper(II)] perchlorate (8) Cu(ClO4)2 Æ 6H2O (115 mg, 0.3 mmol) and (2) (140 mg, 0.6 mmol) were dissolved in 3 mL of EtOH and allowed to stand at 25 C for several hours. After

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this time, blue crystals began to form and were isolated for X-ray analysis. IR (KBr, cm
1): 3292 ms, 3111 m, 2933 w, 1606 vs, 1571 s, 1530 w, 1446 m, 1325 w, 1120 vs, 834 w, 7474 s, 758 m, 624 s, 525 w. Anal. Calc. for Cu(C12H12N2OS)2(ClO4)2: C, 39.65; H, 3.33; N, 7.71. Found: C, 39.70; H, 3.36; N, 7.74%. MS: peaks at m/z = 626 [M
ClO4]+, 526 [M
2ClO4
H]+, 394 [M
ClO4
(2)]+, and 295 [M
2ClO4
H
(2)]+ showed an isotopic pattern indicating the presence of Cu and Cl while one at m/z = 233 [(2) + H]+ did not. MS/MS on m/z = 626, which shows only the 63Cu and 35 Cl isotopes provided further support for this interpretation. The most prominent peak was at m/z = 526; other peaks were observed at m/z = 394, 295, and 233. Visible spectrum (MeCN): kmax (nm), e 675, (1.83). Caution. Perchlorate salts have been known to decompose explosively and care in handling is advised.

4. Supplementary material Crystallographic data for the structural analyses of 1, 2, 4, 6 and 8 have been deposited with the Cambridge Crystallographic Data Center, CCDC 262972–262976. Copies of the data may be obtained free of charge from CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44 1223 336 033; e-mail: [email protected] or www: www.ccdc.cam.ac.uk).

Acknowledgments We acknowledge the support of the NIH (1-R15GM59628-01). The NMR facilities were purchased through grants from NSF (CHE9798077) and the North Carolina Biotechnology Center (Grant 9703-IDG-1007). The mass spectrometer was purchased through a grant from the North Carolina Biotechnology Center (Grant 2001 IDG 1004). We thank Dr. Marcus Wright for assistance with the NMR spectra and Dr. Jian Dai for help with the LC–MS spectra.

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