www.elsevier.com/locate/ica

Inorganica Chimica Acta 359 (2006) 4412–4416

Note

Molecular design, crystal structure, antimicrobial activity andreactivity of light-stable and water-soluble Ag–O bonding

silver(I) complexes, dinuclear silver(I) N-acetylglycinate

Noriko Chikaraishi Kasuga, Rumi Yamamoto, Akihiro Hara,Akifumi Amano, Kenji Nomiya *

Department of Chemistry, Faculty of Science, Kanagawa University, Tsuchiya, Hiratsuka, Kanagawa 259-1293, Japan

Received 13 May 2006; received in revised form 15 June 2006; accepted 19 June 2006Available online 29 June 2006

Abstract

The reaction in water of silver oxide with N-acetylglycine (H2acgly) possessing the partial structure, i.e. the O@C–N–C–COOH moi-ety, afforded light-stable and water-soluble dinuclear silver(I) complex 1{[Ag(Hacgly)]2} (complex 1). X-ray crystallography revealedthat complex 1 in the solid state formed a ladder polymeric structure based on bis(carboxylato-O,O 0)-bridged centrosymmetric Ag2O4

core, which was different from the two previously reported structures of silver(I) glycinate. Complex 1 which only comprises labileAg–O bonding showed a wide range of antimicrobial activities against selected bacteria, yeasts and molds. Complex 1 can also workas an useful silver(I) precursor for novel silver(I) cluster synthesis.� 2006 Elsevier B.V. All rights reserved.

Keywords: Light-stable and water-soluble silver(I) complexes; Ag–O bonding; N-acetylglycinate; Ladder polymer; Antimicrobial activities

1. Introduction

Although silver(I)–N and silver(I)–O bonding com-plexes are potential bioinorganic materials [1–5], most ofthem are light-sensitive especially in solution, and theircharacterization is not easily performed [6]. Preparationsof several water-soluble and relatively light-stable (i.e. sta-ble for a few hours to days at ambient temperature) sil-ver(I) complexes with heterocyclic compounds having anOOC–C–X(X = N or O)–C@O moiety have been reportedrecently such as 1{[Ag(Hpyrrld)]2} (H2pyrrld = 2-pyrroli-done-5-carboxylic acid) [7,8], 1{[Ag(othf)]2} (Hothf = 5-oxo-2-tetrahydrofurancarboxylic acid) [9] and silver(I)4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbox-ylate 1{[Ag(ca)(Hca)]} (camphanic acid, abbreviated as

0020-1693/$ - see front matter � 2006 Elsevier B.V. All rights reserved.

doi:10.1016/j.ica.2006.06.037

* Corresponding author. Tel.: +81 463 59 4111; fax: +81 463 58 9684.E-mail address: nomiya@chem.kanagawa-u.ac.jp (K. Nomiya).

Hca) [10]. Aside from antimicrobial activities, these sil-ver(I) complexes with weak Ag–O bonding have beenrecently also used as useful precursors for formation ofnovel silver(I) clusters such as [Ag(2-Hmba)(PPh3)]4 (2-H2mba = 2-mercaptobenzoic acid) [11], [Ag2(Himdc)-(PPh3)2]2 (H3imdc = imidazole-4,5-dicarboxylic acid) [12]and [Ag(pfbt)(PPh3)]6 (Hpfbt = pentafluorobenzenethiol)[13].

We expected that the partial structure, i.e. the OOC–C–X(X = N or O)–C@O moiety in noncyclic compounds alsocould be used to prepare light-stable silver(I) complexes.We selected the simplest N-acetylamino acid, N-acetylgly-cine (H2acgly), because it is easily accessible and relatedcompound of glycine. Recently, silver(I) complexes withligands which contained glycinate moieties exhibitedmolecular architectures with various intermolecular inter-actions [14,15], therefore, the molecular structure of thecomplex is of interest.

OCOOHO

H

Hothf

NH

COOHO

H

H2pyrrld

OOCOOH

Hca

NH

COOHO

H2acgly

C1

C2C3

C4

H2acala

NH

COOHOC1

C2C3

C4 C5

O

N

NN

N

Me

S

H

Hmtsc

O3

Chart 1. Drawing of the ligands with atomic numbering scheme.

N.C. Kasuga et al. / Inorganica Chimica Acta 359 (2006) 4412–4416 4413

Herein, we report the synthesis, characterization withelemental analysis, TG/DTA, FTIR, solution 1H and 13CNMR spectroscopy, crystal structure and properties ofthe dinuclear silver(I) N-acetylglycinate (complex 1) [16].Antimicrobial activities of complex 1 evaluated by mini-mum inhibitory concentration (MIC: lg mL�1) in a homo-geneous aqueous system are also presented. Also, reportedis synthesis of novel tetranuclear silver(I) cluster with thio-semicarbazone ligand (N 0-[1-(2-pyridyl)ethylidene]mor-pholine-4-carbothio-hydrazide, abbreviated as Hmtsc)[Ag(mtsc)]4 using complex 1 (see Chart 1).

2. Experimental

2.1. General

N-acetylglycine, Ag2O, AgNO3, and organic solventswere obtained from Wako and used as received. The thio-semicarbazone ligand (Hmtsc) was prepared according tothe literature [17]. CHN analyses were performed using aPerkin–Elmer PE2400 series II CHNS/O Analyzer. Infra-red spectra were recorded on a JASCO FT-IR 300 spec-trometer. 1H and 13C NMR spectra were measured usinga JEOL JNM-EX 400 FT-NMR spectrometer or JEOLECP 500 FT-NMR spectrometer. Thermogravimetric(TG) and differential thermal analyses (DTA) wereacquired under air with a temperature ramp of 4 �C min�1

using a Rigaku TG 8101D and TAS 300 data-processingsystem. Antimicrobial activities were estimated as shownelsewhere [18].

2.1.1. Synthesis of silver(I) N-acetylglycate (1)

To 58 mg (0.25 mmol) of Ag2O suspended in 10 mL ofwater was added 59 mg (0.50 mmol) of H2acgly, followedby stirring for 2 h. The colorless solution was filteredthough a folded filter paper (Whatman #5) and the filtrate

was added to 250 mL of acetone drop by drop. The whitepowder formed was collected on a membrane filter (JG0.2 lm), washed with acetone (50 mL · 2) and ether(50 mL · 2), and thoroughly dried in vacuo for 2 h. Thewhite powder, obtained in 70.5% (79 mg scale) yield, wassoluble in water and DMSO, and insoluble in acetone,CH3CN, CH2Cl2, MeOH, EtOAc, CHCl3 and ether. Anal.

Calc. for C4H6O3NAg or [Ag(Hacgly)]: C, 21.53; H, 2.71;N, 6.28. Found: C, 21.45; H, 2.49; N, 6.01%. TG/DTAdata: no weight loss was observed before decomposition.Decomposition gradually began around 171 �C. ProminentIR bands at 1600–400 cm�1 region (KBr disk): 1718w,1637vs, 1595vs, 1499w, 1458w, 1396m, 1299w, 1037w,595w, 530w cm�1. 1H NMR (D2O, 23.8 �C) d 2.03 (3H,s, H4), 3.76 (2H, s, H2). 13C NMR (D2O, 25.7 �C) d24.56 (C4), 45.96 (C2), 176.77 (C3), 179.59 (C1).

Crystallization of 1: After 2-h stirring of Ag2O (58 mg,0.25 mmol) and H2acgly (59 mg, 0.50 mmol) in 20 mL ofwater the reaction mixture was filtered through a folded fil-ter paper (Whatman #5) and the filtrate was concentratedto ca. 10 mL using a rotary evaporator at ca. 30 �C. Theclear solution was placed in a small internal vial and ace-tone was used as an external solvent within a screw-cappedvial for the vapor diffusion at room temperature to givethin platelet crystals in a few days. Characterization withIR, elemental analysis, TG/DTA, 1H and 13C NMR spec-troscopy confirmed that the powder and crystals were thesame compounds. Although we measured ESI-MS spec-trum of complex 1, we were not able to observe the peaksof the dimeric species. This may be attributed to the labileAg–O bonding of complex 1.

2.1.2. Synthesis of [Ag(mtsc)]4 using complex 1 as a

silver(I) source

To a suspension of 0.224 g (0.5 mmol) of complex 1 in100 mL of a mixed solvent (CH2Cl2:EtOH = 4:1) was addedHmtsc (0.26 g, 1 mmol), followed by stirring for 10 min atroom temperature. The white suspension changed to a clearorange solution and the solution was filtered through afolded filter paper (Whatman #5). The filtrate was concen-trated to ca. 4 mL by a rotary evaporator at 30 �C. Thedeep-yellow powder formed was collected on a membranefilter (JG 0.2 lm) and the powder was washed with water,EtOH, and ether (20 mL each) (0.29 g of [Ag(mtsc)]4,78.2% yield). Anal. Calc. for C48H60N16S4O4Ag4 or[Ag(mtsc)]4: C, 38.83; H, 4.07; N, 15.09. Found: C, 39.33;H, 4.51; N, 14.72%. TG/DTA data: no weight loss underdecomposition. Decomposition began at around 190 �C.Some predominant IR bands in the 1800–400 cm�1 region(KBr disc): 1585m, 1482m, 1455s, 1427vs, 1356s, 1301s,1283m, 1265m, 1207vs, 1158w, 1118s, 1066s, 1030s, 976m,884s, 838m, 800m, 781s, 743m, 719m, 670m, 633m, 559m.1H NMR (CDCl3, 23.6 �C) d 2.09 (3H, br, H7), 3.60 (4H,br, H10/H11), 3.80 (4H, br, H9/H12), 7.19 (1H, br, H2),7.50 (1H, br, H4), 7.69 (1H, br, H3), 8.48 (1H, br, H1).The tetranuclear structure was also confirmed by single-crystal X-ray analysis [19].

Fig. 1. (a) Molecular structure of 1 showing Ag2O4 core (symmetryoperation i = �x, �y, �z; ii = �1 + x, 1 + y, z; iii = 1 � x, �1 � y, �z).Selected distances (A) and angles (�): Ag1–O1 2.165(3), Ag1–O2i 2.210(3),Ag1–O2ii 2.419(3) A; O1–Ag1–O2i 164.17(7), O1–Ag1–O2ii 164.17(7), O1–Ag1–Ag1i 84.45(10) and O2ii–Ag1–Ag1i 158.09(5)�. (b) Coordinationladder polymer viewed along the a-axis. (c) Side view of ladder polymers.

4414 N.C. Kasuga et al. / Inorganica Chimica Acta 359 (2006) 4412–4416

2.2. X-ray crystallography

The intensity data were collected at 90 K on a RIGAKUMercury CCD diffractometer. The structure was solved bydirect methods (CRYSTALSTRUCTURE version 3.7.0), andrefined by a full-matrix least-squares on F2 (SHELXTL ver-sion 5.10). Crystal data for complex 1: C8H12N2O6Ag2;M = 447.94, triclinic, space group P�1, a = 3.800(3) A,b = 4.681(4) A, c = 17.09(2) A, a = 77.36(7)�, b =82.93(7)�, c = 81.84(7)�, V = 292.4(5) A3, Z = 1, Dc =2.54 g cm�3, l(Mo Ka) = 3.370 mm�1, 2998 reflections col-lected, 1277 independent (Rint = 0.0219), R1 = 0.0214,wR2 = 0.0501 for I > 2r(I), R1 = 0.0238, wR2 = 0.0514,Goodness-of-fit = 1.105 for all data.

3. Results and discussion

The 2:1 molar-ratio reaction of N-acetylglycine andAg2O in water gave complex 1 as colorless thin-platemica-like crystals in 67.0% (75 mg scale) yield. The prepa-ration of complex 1 by mixing aqueous or methanol solu-tion of AgNO3 or AgClO4 and N-acetylglycine waspreviously reported, but the X-ray crystallography andproperties such as light-stability and water-solubility werenot described [16]. In the present synthesis, Ag2O was usedinstead of AgNO3 or AgClO4, since we have found usage ofAgNO3 has sometimes caused contamination of the NO3

�

ion into the product, which was difficult to remove. Whencomplex 1 was dissolved in water no color-change occurredfor several days at room temperature. In contrast, when theisolated powder of silver(I) glycinate was dissolved inwater, the solution turned to black suspensions immedi-ately [6]. The composition and molecular formula of 1 wereconsistent with elemental analysis, TG/DTA, FTIR andsolution (1H and 13C) NMR spectroscopy.

The silver(I) complexes with amino-acid ligands with Nand O donor atoms and without an S atom have been clas-sified into four types (I–IV) based on the bonding modes ofthe silver(I) center; type I with only Ag–O bonds, types IIand III with both Ag–O and Ag–N bonds and type IV withonly Ag–N bonds [6]. Two crystal structures have beenreported for silver(I) glycinate [6,20]. Silver(I) glycinateanhydride was a helical polymer belonging to type III, inwhich each silver(I) ion was bound to the Ocarboxyl atomof one gly� ligand and to the Namino atom of another,i.e. the two-coordinate N–Ag–O bonding units wererepeated [20]. On the other hand, silver(I) glycinate hydratewas a helical polymer belonging to type II, in which alter-nate silver(I) ions were bound to two Ocarboxyl and twoNamino atoms, respectively, i.e. the O–Ag–O and N–Ag–N bonding units were alternately repeated [6]. X-ray struc-ture analysis revealed that the structure of complex 1 wasdifferent from those of silver(I) glycinate belonging to typesII and III. The molecular structure of complex 1 is similarto that of the previously reported 1{[Ag(R,S-othf)]2} poly-mer with a heterocyclic ligand [9] and, therefore, belongsto type I. Three oxygen atoms were coordinated to Ag1

(Ag1–O1 2.165(3), Ag1–O2i 2.210(3), Ag1–O2ii 2.419(3) A,symmetry operations i = �x, �y, �z and ii = �1 + x,1 + y, z). The Ag1. . .Ag1i separation (2.805(3) A) wasshorter than that of metallic silver (2.88 A) [21]. The planarAg2O4 core formed by Ag1, Ag1i, O1, O2, O1i and O2i wasconnected through O2 (O2ii and O2iii, symmetry operationiii = 1 � x, �1 � y, �z) (Fig. 1(a)). This Ag–O bondingmode of this silver(I) carboxylate was type d, which wasclassified by Mak [22]. As a result, a planar ladder polymer

1{[Ag(Hacgly)]2} based on bis(carboxylato-O,O 0)-bridgedcentrosymmetric [Ag(Hacgly)]2 dimers running across thecrystallographic b and c axes was formed (Fig. 1(b)). Inthe polymer the carboxylato group of the Hacgly� ligandserved in a symmetric syn–anti bridging mode [23]. The

Table 1Antimicrobial activities of silver(I) complexes and related compounds evaluated by minimum inhibitory concentration (MIC; lg mL�1)

1{[Ag(Hacgly)]2} 1{[Ag(Hgly)]2 Æ H2O}a1{[Ag(R,S-Hpyrrld)]2}b

1{[Ag(R,S-othf)]2}c AgNO3d Ag2Od

Escherichia coli 15.7 62.5 15.7 7.9 6.3Bacillus subtilis 62.5 125 31.3 62.5 100 500Staphylococcus aureus 62.5 62.5 31.3 62.5 62.5 1000Pseudomonas aeruginosa 125 62.5 15.7 31.3 62.5

Candida albicans 15.7 15.7 7.9 15.7 >1600Saccharomyces cerevisiae 15.7 15.7 15.7 7.9 1600

Aspergillus niger 15.7 31.3 15.7 7.9 >1600Penicillium citrinum 15.7 62.5 15.7 7.9 >1600

a Ref. [6].b Ref. [8].c Ref. [9].d Ref. [18].

N.C. Kasuga et al. / Inorganica Chimica Acta 359 (2006) 4412–4416 4415

distance of the nearest silver(I) atoms between the ladderswas 3.361(3) A (dotted lines in Fig. 1(c)), indicating thatthere was a van der Waals contact between the silver(I)atoms. The distances of the disordered O3 atoms and N1were in the range of 2.843(7)–2.936(6) A, indicating thathydrogen bonds were formed between the ladders throughO3 and N1 as shown in dashed lines in Fig. 1(c).

Water-soluble Ag–O bonding complexes such as

1{[Ag(R,S-Hpyrrld)]2} and 1{[Ag(R,S-othf)]2} reactedwith the Hmtsc in a 4:1 mixed CH2Cl2/EtOH solvent togive an orange powder of the tetranuclear cluster,[Ag(mtsc)]4 [19]. To further examine the reactivity of

1{[Ag(Hacgly)]2}, the same reaction using complex 1 wasperformed and we confirmed that this silver(I) complexgave the same product in good yields which was character-ized by elemental analysis, FTIR and 1H NMR [19].

Antimicrobial activities of the silver(I) complexes arelisted in Table 1. Water-insoluble Ag2O showed modestactivity against two bacteria, whereas, the aqueous Ag+

ion, as aqueous AgNO3, showed effective activity againstGram-negative bacteria (Escherichia coli and Pseudomonas

aeruginosa), modest activity against Gram-positive bacteria(Bacillus subtilis) and no activity against yeasts and molds[18]. As expected for Ag–O bonding complexes, complex 1

showed a wide spectrum of effective antimicrobial activitiesagainst the selected bacteria, yeasts and molds, whose effec-tiveness was as much as that for silver(I) complexes,

1{[Ag(R,S-Hpyrrld)]2} or 1{[Ag(R,S-othf)]2} [8,9]. Theseresults support our hypothesis that the weak bondingwhich would be readily replaced by substrates includingbiomolecules would be the key role for antimicrobial activ-ities of silver(I) complexes.

In summary, the reaction of N-acetylglycine with Ag2Ogave light-stable and water-soluble silver(I) complex. Thisresult indicated that linear compounds with the OOC–C–X(X = N or O)–C@O moiety were also candidates asligands to form light-stable and water-soluble Ag–O bond-ing complexes. Preparation of other silver(I) complexeswith N-acetylamino acids is underway such as N-acetylala-nine (H2acala).

Acknowledgement

This work is supported by a High-tech Research CenterProject from the Ministry of Education, Culture, Sports,Science and Technology, Japan.

Appendix A. Supplementary data

The details of the crystal data have been deposited withCambridge Crystallographic Data Centre as Supplemen-tary Publication No. CCDC 601868 for 1. Supplementarydata associated with this article can be found, in the onlineversion, at doi:10.1016/j.ica.2006.06.037.

References

[1] A.D. Russell, W.B. Hugo, Prog. Med. Chem. 31 (1994) 351.[2] J.L. Clement, P.S. Jarrett, Metal-Based Drugs 1 (1994) 467.[3] M.C. Gimeno, A. Laguna, Comprehensive Coordination Chemistry

II, vol. 6, Elsevier, Oxford, 2004, p. 911.[4] C.F. Shaw III, in: N.P. Farrell (Ed.), Uses of Inorganic Chemistry in

Medicine, RSC, UK, 1999, Chapter 3, p. 26.[5] Q.L. Feng, J. Wu, G.Q. Chen, F.Z. Cui, T.N. Kim, J.O. Kim, J.

Biomed. Mater. Res. 52 (2000) 662.[6] K. Nomiya, H. Yokoyama, J. Chem. Soc., Dalton Trans. (2002)

2483.[7] K. Nomiya, S. Takahashi, R. Noguchi, S. Nemoto, T. Takayama,

M. Oda, Inorg. Chem. 39 (2000) 3301.[8] K. Nomiya, S. Takahashi, R. Noguchi, J. Chem. Soc., Dalton Trans.

(2000) 4369.[9] K. Nomiya, S. Takahashi, R. Noguchi, J. Chem. Soc., Dalton Trans.

(2000) 1343.[10] N.C. Kasuga, A. Sugie, K. Nomiya, Dalton Trans. (2004) 3732.[11] R. Noguchi, A. Hara, A. Sugie, S. Tanabe, K. Nomiya, Chem. Lett.

34 (2005) 578.[12] R. Noguchi, A. Sugie, A. Hara, K. Nomiya, Inorg. Chem. Commun.

9 (2006) 107.[13] R. Noguchi, A. Sugie, A. Hara, K. Nomiya, Inorg. Chem. Commun.

9 (2006) 60.[14] M. Barcelo-Oliver, A. Tasada, J.J. Fiol, A. Garcia-Raso, A. Terron,

E. Molins, Polyhedron 25 (2006) 71.[15] A. Erxleben, Inorg. Chem. 40 (2001) 2928.

4416 N.C. Kasuga et al. / Inorganica Chimica Acta 359 (2006) 4412–4416

[16] L. Antolni, L. Menabue, M. Saladini, Inorg. Chim. Acta 46 (1980)L77.

[17] J.P. Scovil, Phosphorus Sulfur Silicon 60 (1991) 15.[18] K. Nomiya, K. Tsuda, T. Sudoh, M. Oda, J. Inorg. Biochem. 68

(1997) 39.[19] K. Onodera, N.C. Kasuga, T. Takashima, A. Hara, A. Amano, H.

Murakami, K. Nomiya (in preparation, CCDC No. 294754).

[20] C.B. Acland, H.C. Freeman, J. Chem. Soc., Chem. Commun. (1971)1016.

[21] A.F. Wells, Structural Inorganic Chemistry, fourth ed., OxfordUniversity Press, London, 1975, p. 1015.

[22] X-M. Chen, T.C.W. Mak, Polyhedron 14 (1991) 1723.[23] C.J. Carrell, H.L. Carrell, J. Erlebacher, J.P. Glusker, J. Am. Chem.

Soc. 110 (1988) 8651.