Interactions of guanidinium with benzene-sulphonic, -phosphonic and -arsonic acids and several of their nitro-derivatives

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Abstract

The supramolecular interactions of the planar guanidinium cation (C(NH2)3+) with benzenesulphonate (1), -phosphonate (2) and -arsonate (3) anions, and several of their 3- and 4-nitro-substituted derivatives is reported. In all cases well-defined crystalline materials, containing hydrogen-bonded networks with quasi-hexagonal sheet lattices were formed. However, the unsubstituted sulphonate (1) formed a 1:1 guanidinium:sulphonate bilayer structure, whilst the unsubstituted phosphonate (2) and arsonate (3) formed 2:1 guanidinium:phosphonate/arsonate single-layer structures with water occluded within the crystal voids. The additional H-bonding interactions resulting in distortion of the crystal voids in (2)/(3) as compared to the symmetrical hexagonal-form in (1). In the case of the nitro-substituted sulphonate derivatives, the 1:1 bilayer structure of the parent (1) was retained for the 3-nitrobenzenesulphonate (4), but transformed to a 1:1 single-layer system for the 4-nitrobenzenesulphonate (6). The reverse was observed for the nitrated phosphonic acids, whereby the 4-nitrobenzenephosphonate anion in (5) caused little disruption to the 2:1 single-layered structure and quasi-hexagonal sheet seen in (2), but the 3-nitrobenzenephosphonate caused a breakdown of the network forming a new, complex ribbon system (7). The greater complexity of the P/As (−2) structures compared to the S (−1) structure is attributed to the higher charge on the former anions providing additional opportunities for H-bonding. The observation of such interactions clearly indicates the likelihood of such species interacting with biologically-important arginine residues in vivo with concomitant unintended, but likely, toxic consequences.

Introduction

The planar guanidinium cation, C(NH2)3+ (Fig. 1a), plays a crucial role in directing the formation of higher-order biological structures, and is found in the side chains of arginine-rich histone proteins (see amino-acid arginine in Fig. 1b). There has been considerable interest in the development of artificial arginine receptors due to the key role arginine plays in numerous biological processes controlling gene regulation, glycoprotein targeting and vesicle transport [1].

The tetrahedral anions, sulphonate (RSO3-), phosphonate (RPO32-, RPO3H-), and arsonate (RAsO32-, RAsO3H-), all exhibit four oxygen-rich faces, containing two or three hydrogen bond acceptors (A), see Fig. 1c. Most of the biological properties of the guanidium cation are related to its strong basicity in aqueous media, and the richness of its intermolecular interactions [2]. The guanidinium cation has a complementary geometry and is able to interact with these anions, and many others [2], through donor (D)–acceptor (A) (N–H⋯O) hydrogen-bonding, and if all three anions are present, it is reasonable to expect that they will compete for binding to C(NH2)3+. However, whilst the interaction of sulphonic acids with guanidinium cation has attracted much activity in recent years [3], [4], [5], [6], supramolecular interactions of organic phosphonate groups have been overshadowed by the greater interest in metal phosphonates [7], [8], [9], [10], [11], [12], with the exception of one study by Weakley [13], and there are no reports in the literature of the interaction of guanidinium cation with arsonates.

The lack of study on phosphonates and arsonates is quite surprising. In the former case, it is well known that the guanidinium cation plays a vital role in the interaction of molecules possessing a phosphate moiety (e.g. adenosine diphosphate (ADP)), by participating in the enzymatic binding of anionic substrates (e.g. arginine kinase [14], creatine kinase [15]), or the dedicated interaction of biopolymers, which make up the winding of DNA around an arginine site to produce a nucleosome particle [16], [17]. In contrast, the arsenic-based compounds have become accepted agents for cancer chemotherapy, providing high rates of remission for some cancers such as acute promyelocytic leukaemia (APL) [18], [19], [20], [21], [22], and organic ingredients based on As are commonly used as feed additives in poultry farming to increase weight gain by preventing bacterial and parasitic infections. The three major arsenic-compounds used for this purpose being arsenilic acid (4-aminophenylarsonic acid), roxarsone (4-hydroxy-3-nitrophenylarsonic acid), and nitarsone (4-nitrophenylarsonic acid) [23], [24].

It is known that arsonate (together with phosphonate and sulphonate) species are metabolised within mitochondria, where it is taken up as As(V), rapidly reduced to As(III), which has a greater toxicity than As(V), and the product(s) exported back to the cytosol [25]. It is also known that arsonate species can influence oxidative phosphorylation by binding to the F0/F1 ATP-synthase more efficiently than phosphonate, leading to the production of ADP-arsenate which, unlike ATP, is rapidly hydrolysed and unable to form stable high-energy compounds [26]. Thus, it has been suggested that as a result of the structure and charge similarities of R-PO32-, R-AsO32-, and R-SO3-, arsonate and sulphonate can compete against phosphonate for binding to F0/F1 ATP-synthase leading to the inhibition of ATP production [27].

This paper describes a systematic study of the interaction of the guanidinium cation (C(NH2)3+) with selected benzene-oxy anions including, sulphonate (RSO3-), phosphonate (RPO32-) and arsonate (RAsO32-), and several of their 3- and 4-nitro (NO2) anionic derivatives (Fig. 2). An analysis of the structural features of the crystalline materials isolated has been used to assess the influence of the charge difference (RSO3- vs. RPO32-) and the strengths of the H-bonding interactions between the guanidinium cation and the S, P or As anions on the supramolecular motifs observed.

Section snippets

Chemical reagents

The following reagents were obtained commercially and used without further purification: 4-nitroaniline (98%, Merck), guanidine hydrochloride (99%, Aldrich), guanidinium carbonate (99%, Aldrich), benzenesulphonic acid (98%, Aldrich), benzenephosphonic acid (98%, Aldrich), benzenearsonic acid (98%, Aldrich), 4-nitrobenzenesulphonic acid (99%, Tokyo Chemical Industry (TCI) UK Ltd.), 3-nitrobenzenesulphonic acid (99%, TCI), 3-nitrobenzenephosphonic acid (99%, TCI), sodium tetrafluoroborate (GPR,

Preparation of guanidinium benzene-oxy acids

The guanidinium benzenesulphonate compounds [(C(NH2)3]+·[R-SO3] (where R = C6H5 (1), 3-NO2C6H4 (4), and 4-NO2C6H4 (6)) were all synthesized by reaction of a 1:1 mol ratio of guanidinium chloride and benzenesulphonic acid in a 1:1 water: ethanol solution, according to the method of Ward et al. [4], [6]. Guanidinium benzenephosphonate dihydrate (2) was prepared following the method of Weakley [13], using a 1:1 M ratio of guanidinium carbonate: benzenephosphonate dissolved in a hot solution of 1:1

Concluding remarks

From the systematic structural study of the crystalline materials isolated from the reaction of guanidinium salts with benzene-sulphonic, -phosphonic and -arsonic acids, the nature and strengths of the hydrogen-bonding interactions between the guanidinium cation ([C(NH2)3]+) and the benzene-oxy acids were examined. In each case a R3,6(12) quasi-hexagonal sheet, composed of six smaller R2,2(8) H-bonded rings, was formed; the latter constructed from pairs of N–H⋯O–D interactions. The strength of

Supporting information

CCDC Nos. 796680–796683 contain the supplementary crystallographic data for this paper (compounds (2), (3), (5) and (7)). These data are available free of charge via www.ccdc.cam.ac.uk/data_request/cif, (or from The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: +44 1223 336 033).

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