Metal Complexes as Self-Indicating Titrants for ... - ACS Publications

Article pubs.acs.org/IC

Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

Metal Complexes as Self-Indicating Titrants for Acid−Base Reactions in Chloroform Antonino Giannetto,*,† Massimiliano Cordaro,†,‡ Sebastiano Campagna,† and Santo Lanza† †

Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, V.le F. Stagno d’Alcontres 31, 98166 Messina, Italy ‡ CNR-ITAE, Istituto di Tecnologie Avanzate per l’Energia “Nicola Giordano”, 98126 Messina, Italy S Supporting Information *

ABSTRACT: The paper reports an unprecedented spectrophotometric determination of amines in chloroform, in which amines are not transformed into colored derivatives. This result has been achieved by exploiting the acid−base properties of the tight-ionpaired metal complexes [(HR2DTO)Pt(H2R2DTO)][Cl], which are able to donate a HCl molecule to an amine, giving rise to an ammonium salt and to the neutral complexes [(HR2DTO)2Pt]. The circumstance that [(HR 2 DTO)Pt(H 2 R 2 DTO)][Cl] and [(HR2DTO)2Pt] species show different absorptions in the visible region of the electromagnetic spectrum enables the aforementioned platinum complexes to behave as self-indicating titrants in the spectrophotometric determination of aliphatic amines, which are known to be UV−vis transparent. The new method has been tested by determining a series of fatty amines in the bulk and gave excellent results. The limits of applicability of this method (pKa > 4) were found by testing a series of benzodiazepines.

■

INTRODUCTION Molecules containing hydrogen bond donor groups have played a crucial role in the field of noncovalent coordination of anions.1−5 In particular, thioamide- and thiourea-based receptors6,7 have been shown to be suitable molecular systems for giving rise to effective supramolecular interactions with anions of various complexities. However, secondary dithiooxamides, whose structure is strictly similar to that of the aforementioned classes of compounds (Figure 1) have never been exploited as synthons to be inserted into properly designed anion receptors.

chelating system. For example, the reaction of cis-Pt(Me2SO)2Cl2 with a double molar amount of a secondary dithiooxamide in chloroform sequentially produces the monoand bis-chelated platinum(II) complexes, as shown in Scheme 1. According to Scheme 1, a tooth of the sulfur chelating system of the dithiooxamide removes one of the two sulfoxides in cisPt(Me2SO)2Cl2; the subsequent ring closure produces the exit of the chloride ion from the coordination sphere of platinum(II). However, the leaving chloride remains as a guest in the amidic system of the S,S-coordinated dithioxamide. This means that the NH frames of the secondary dithiooxamide become hydrogen bond donor groups as a consequence of the chelation of the metal through the S,S system of the secondary dithiooxamide. This is in part the result of the polarization of N−H groups due to electron withdrawal following the coordination of the sulfur system to the metal; in addition, the coordination forces the ligand into a conformation suitable for an effective interaction of the N−H HBD groups with the Cl− anion. As a matter of fact, the chelation of platinum triggers the HBD properties of the amidic hydrogens of a secondary dithioxamide. Similar effects of a metal ion on the binding properties of some anion receptors have been already observed: coordinatively unsaturated metal complexes might provide cooperative binding with urea- or thiourea-based receptors

Figure 1. Species containing hydrogen bond donor groups in HN(R)−C(S)− fragments.

However, dithioxamides contain two amidic N−H frames which are potentially hydrogen bond donor (HBD) groups, but these species do not interact with anions; probably the tilted array of the two CSNR frames around the pivot bond makes the interaction of the two HBD amidic groups with an anion unstable. The mutual position of NH groups changes when a secondary dithiooxamide links a metal ion through the sulfur © XXXX American Chemical Society

Received: December 6, 2017

A

DOI: 10.1021/acs.inorgchem.7b03081 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Scheme 1. Sequential Synthesis of [Pt(H2R2DTO)2][Cl]2 Tight Ion Pair (I)

Scheme 2. Proposed Mechanism for the δ ⇌ λ Conformational Change in One of the PtSCCS Ringsa

a

The same process also rules δ ⇌ λ conformational change in the other DTO chelate ring (right side in the molecular formulas).

Scheme 3. (1) Equilibrium Process between [Pt(H2R2DTO)2][Cl]2 (I) and Brønsted Bases (:B) in Chloroform and (2) Equilibrium Process between [(HR2DTO)Pt(H2R2DTO)][Cl] (II) and Brønsted Bases (:B) in Chloroform

(scorpionate effect)8 and metal ions can act as templates as well, which through a preorganization of binding sites lead to a more effective anion recognition.8−13 The metal complex labeled as I in Schemes 1 and 2 is an extensively associated tight ion pair: the two chloride ions are paired by the positive charges of the metal ion which are delocalized in the dithioxamide ligands (molecular formulas in Schemes 1 and 2). Furthermore, it has been shown that the molecular plane in I is a symmetry plane, notwithstanding the chiral torsion of the two NCS frames around the pivot bond;

also, the monofunctional ion pair II depicted in Scheme 2 shows only one pattern for R groups in the proton spectra. In any case, the symmetrization of NMR signals in the proton spectra of both I and II (Scheme 3) is a consequence of the fast conformational changes of the S,S-coordinated dithiooxamides. Such a conformational change follows the reversible dissociation of an HCl molecule, which alternatively rebounds between the N···H−N basic site of I, as well as of II, and the solvent (Scheme 2). B


Article

Inorganic Chemistry It has been observed that even a weak Brønsted base, such as a solvent containing donor atoms (Me2SO, ROH, acetonitrile, and so on), is able to remove HCl from the ion pair of either I and II; thus, in a low-polarity noncoordinating solvent and in the presence of a Brønsted base (:B), the acid−base equilibria shown in the Scheme 3 take place. In other words, the above “acid−base-like” interaction concerns the exchange of HCl between the basic sites of the NHN system of either II or III and the base :B exploited. Actually the most surprising aspect of the above acid−base system is that N2H2Cl acidic sites in either II or I exchange HCl with the solvent chloroform, which is a species lacking donor atoms typical of a Brønsted base. Equilibria 1 and 2 in Scheme 3 have already been studied, either changing the electron disposal on nitrogen chelating systems of I−III14 or changing the base strength of :B (:B = pyridines having a wide pKa range).15 The above referred studies suggest that in the δ ⇌ λ conformational change of the PtSCCS chelate ring (Scheme 2) the solvent strongly affects not only the entropy factor but also the enthalpy factor. In particular, UV measurements at variable temperature of the equilibrium constants for the process

Figure 2. Spectral changes in the course of the process [(HR2DTO)Pt(H2R2DTO)][Cl] + :B ⇌ [Pt(HR2DTO)2] + [BH][Cl] (R = benzyl; :B = 1-hexylamine; solvent = chloroform). In the starting spectrum the concentration of [(HR2DTO)Pt(H2R2DTO)][Cl] is 1 × 10−4 mol dm−3.

By selecting the proper wavelength, it is possible to obtain the equilibrium constant value for the process under examination. We found that the values of the equilibrium constants of processes 1 and 2 in Scheme 3 became greater (i) when the basicity of :B increases and (ii) when the acidity of ion pairs increases. What was said above is demonstrated by a series of equilibrium processes which have provided typical curves whose shapes were ruled by the value of the relative equilibrium constant (Figure 3).

[(HEt 2DTO)Pt(H 2Et 2DTO)]Cl + HCl ⇌ [Pt(H 2Et 2DTO)2 ]Cl 2

gave an observed ΔH = −146.3 ± 9.7 kJ mol−1. At a first glance, this ΔHobs value appears to be too high an energy contribution for the sole interaction between an HCl molecule and a N−H···N basic site of a S,S-Pt coordinated dithioxamidate; however, it has been argued15 that the preponderant part (about 70−85%) of the measured enthalpy contribution can be attributed to the chloroform solvating complexes I−III and HCl molecules, which are engaged in a series of acid−base equilibria including ion association, ion pairing, and host−guest interactions. In other words, the interaction between HCl released from the ion pair I (Scheme 2) with chloroform, which cannot exceed a few kJ per mol of HCl,16 may reach our experimentally determined ΔHobs if the system I/II/III/HCl dynamically interacts with a number of chloroform molecules large enough to give an energy lowering comparable to the magnitude of a strong bond. The interaction between HCl and chloroform may occur through a cooperative effect of halogen bonding17 as a complement of hydrogen bonding.16 Such interactions, which have been observed as anion/chloroform clusters in the solid state,18 may also be responsible for the dynamic supramolecular system I/II/III/HCl conjectured above. In conclusion, the acid−base behavior of species I and II substantially depends on the fact that secondary dithiooxamides coordinated to a transition metal behave as anion receptors, being able to achieve contact ion pairs with halides (I and II species), which may be used as self-indicating titrants in the determination of amines in chloroform.

■

Figure 3. Variation of the absorbance during the process [(HR2DTO)Pt(H2R2DTO)][Cl] + :B ⇌ [Pt(HR2DTO)2] + [BH][Cl] (R = benzyl; solvent = chloroform; :B = (a) pyridine (Kc = 2.16), (b) 3methylpyridine (Kc = 9.18), (c) 3,6-lutidine (Kc = 63), (d) 1hexylamine (Kc > 106)). In each titration curve absorbance values have been measured at 447 nm. In all cases the total concentration of platinum was 1 × 10−4 mol dm−3.

Looking at Figure 3, one can see that, when the value of the equilibrium constant Kc is very high, it is easy to determine the equivalence points of the processes (curve d). In other words, by using a suitable complex [(HR2DTO)Pt(H2R2DTO)][Cl] (R = Alkyl), it becomes possible to determine the concentration of any alkylamines in chloroform, by simply adding to a solution of the amine of unknown concentration known volumes of the suitable [(HR2DTO)Pt(H2R2DTO)][Cl] species. For example, spectral changes shown in Figure 4 are obtained by addition of [(HR2DTO)-

RESULTS AND DISCUSSION

Figure 2 shows the spectral changes referred to process 2 in Scheme 3 when known amounts of amine are added to a known quantity of the complex [(HR2DTO)Pt(H2R2DTO)][Cl] (R = ethyl, 1; R = benzyl, 2); in the course of the titration the total concentration of Pt remains constant. C


Article

Inorganic Chemistry

Figure 4. (a) Spectral changes by addition of [(HR2DTO)Pt(H2R2DTO)][Cl] (R = benzyl) to 1-hexylamine. (b) Detection of the equivalence point, where absorbance values have been measured at 520 nm. The measured absorbance values lie in the straight lines of graph (b) also in the proximity of the equivalence point.

decarboxylation of amino acids.19 In addition, these substances are important active ingredients of synthetic psychiatric drugs20 and sometimes are exploited as drugs of abuse.21 In addition, both aromatic and aliphatic amines are very dangerous organic pollutants.22,23 Thus, it is easily understandable why the analytical determination of these substances is generally considered a powerful tool in the protection of the environment and public health as well as in biomedical investigations. The most suitable methods for the quantitative determination of the aforementioned organic compounds are based on chromatographic separation coupled with mass spectrometry (HPLC-MS) methodologies. However, this procedures involves expensive instrumentation which does not allow easy and rapid mass screenings. In this respect, photometric, fluorimetric, and colorimetric methods seem to be more suitable in that they require low-cost instrumentations and are easily executed. Unfortunately, aliphatic amines generally are not light-absorbing substances and require a previous transformation into colored derivatives, which can be detected by means of procedures based on light-absorbing and/or lightemitting techniques. In the past, a series of basic papers have been produced aiming to demonstrate that the spectrophotometric determination of amines after derivatization into colored compounds was a reliable, sensitive, and reproducible analytical technique. Such papers mostly referred to amines transformed in Meisenheimer intermediates,24 in charge transfer complexes,25−28 in colored ammonium ion pairs,29,30 in nitrogen donor ligands able to give rise to colored metal complexes,29,31−33 and so on.34−36 A great amount of papers dealing with spectrophotometric, fluorimetric, and colorimetric methods aimed at the determination of biogenic amines contained in biological matrices as well as in dosage forms have been systematically reported in the specialized literature; they will be mentioned whenever it will be necessary. Such papers generally exploit determination procedures which show little changes with respect to those described in the official methods.37,38 The method proposed here for the spectrophotometric determination of amines differs from those generally reported both in its theoretical bases and in experimental procedures. Nonetheless, the results provided are good, reproducible, easily obtained and finally have high sensitivity, at least when the amines to be determined are basic enough (pKa > 7.5). In this respect, the proposed method appears to be suitable also for the spectrophotometric determination of many mutagenic and carcinogenic foodborne heterocyclic amines (HCAs), in which the N1 of the 2-

Pt(H2R2DTO)][Cl] (R = benzyl) to a solution of 1hexylamine. The first spectrum in Figure 4 is coincident with the baseline in that the amine solution is not light-absorbing in the explored spectral range. Upon addition of [(HR2DTO)Pt(H2R2DTO)][Cl] (II) to the chloroform solution of amine, a spectrum appears which is attributable to [Pt(HR2DTO)2] (III). When the quantity of II added is equivalent to the amount of amine, the spectrum is mainly produced by III. After equivalence, the species II added in excess no longer reacts; thus, the increased absorbance in the spectrum is due only to species II. By plotting of the optical densities measured at a proper wavelength vs concentration of total complex added, a plot as in Figure 4b is obtained so that the equivalence point is detectable without any ambiguity. This happens when the titrated amines have pKa > 7.5. As a first approach, we tested the reliability of the method proposed here for the spectrophotometric determination of amines in chloroform by determining in the bulk the following fatty amines: 1-aminobutane, 1-aminohexane, 1-aminododecane, diethylamine, triethylamine, and ethylenediamine. Such amines have been chosen because they vary in both the alkyl chain length and the substituents on the nitrogen. Finally, ethylenediamine was tested as a model of the bifunctionalized biogenic amines putrescine and cadaverine. Each amine underwent five independent determinations according to the procedure described in the Experimental Section. The results are collected in Table 1. Table 1. Recovery of Amines from the Bulk by Means of the Determination Method Proposed Here amine 1-aminobutane 1-aminohexane 1-aminododecane diethylamine triethylamine ethylenediamine

found (%) 99.5 100.1 98.8 100.3 99.7 99.6

± ± ± ± ± ±

0.31 0.2 0.4 0.1 0.5 0.4

As one can see from the data in Table 1, the recovery of the amines has been very good in all cases. Many aliphatic amines with low molecular weight are biogenic and are synthesized by microbial, vegetable, and animal metabolisms. In food and beverages they are formed by the enzymes of the raw material or are generated by microbial D


Article

Inorganic Chemistry

the erroneous impression that benzodiazepines have a relatively high abuse liability among recreational drug users. The abuse or misuse of benzodiazepines is internationally widespread, which means that any forensic laboratory may encounter a range of these compounds. Therefore, the development of rapid, easily performed, sensitive, and reproducible spectrophotometric methods for their preliminary screening may relieve the burden of criminology laboratories working with more sophisticated but more expensive and laborious HPLC/MS instruments. Generally, nonaqueous titration and spectrophotometric methods for the determination of benzodiazepines in raw materials and dosage forms are recommended. In fact, benzodiazepines and their metabolites have extinction coefficients on the order of 104 dm3 mol−l cm−l, which allow determination of these compounds to the microgram per milliliter level with conventional spectrophotometers.43,44 Since the spectral region explored for the determination is affected by too many interferences from other absorbing substances, improved results have been obtained with difference45 or derivative46 spectrophotometry. Also, extractive spectrophotometric methods based on the formation of 1:1 ion-association complexes of benzodiazepines with acidic dyes have been carried out.47 Finally, the capability of benzotiazepines to form intensely colored metal complexes has been exploited for their spectrophotometric determination.48 We have purchased from local suppliers the dosage forms of the following benzodiazepines: olanzapine (3; Teva, 20 mg), flurazepam hydrochloride (4; flunox, 30 mg, Teofarma), triazolam (5; halcion, Pfizer, 0.25 mg tablets), diazepam (6; valium, Roche, 5 mg tablets), and bromazepam (7; lexotan, Roche, 6 mg tablets) (Figure 6). As a preliminary experiment, samples of tablets of each investigated benzodiazepine were finely powdered. A portion of each powdered sample was suspended in 1 mL of CDCl3 with magnetic stirring. Proton spectra of resulting solution showed that only pure benzodiazepine or BZD·HCl was extracted. Only triazolam showed a low quantity of other species whose signals were different from those attributable to the benzodiazepine molecule, in particular in the methylene region. This probably is due to some excipient contained in the tablets (dihexyl sodium sulfosuccinate, food colorant E132 “indigo carmine”), which however contain groups not basic enough to interfere in the titration. The results of the benzodiazepines 3−7 in tablets are reported in Table 3. The shape of the titration curves of 5−7 (Figure 7) indicates that the basicity of these systems is lower than that of pyridine (pKa = 5.13).

aminoimidazo[4,5-f ] ring is characterized by a pKa value ranging around 7.0.39−42 However, many heterocyclic species contain basic nitrogen donor atoms whose pKa values occur in the range 7−5. We have determined in the bulk the series of pyridines reported in Table 2. In order to obtain fairly good results, the titrations of Table 2. Recovery of Pyridines from the Bulk by Means of the Determination Method Proposed Here pyridine

pKa

found (%)

H 3-methyl 4-methyl 3,4-dimethyl

5.17 5.63 6.05 6.56

103.1 97.9 98.7 100.5

± ± ± ±

2.5 1.8 0.9 0.5

such kinds of compounds require greater care in handling data because the measured absorbance values in the proximity of the equivalence point deviate from the straight lines of the graph (Figure 5).

Figure 5. Titration curve obtained by adding [(HR2DTO)Pt(H2R2DTO)]+[Cl−] (R = benzyl) to a pyridine (pKa = 5.17) solution. Absorbance values have been measured at 520 nm.

With the aim of verifying the applicability limits of the method, we attempted to determinate benzodiazepines (BZDs) in tablets as a possible test of quality control for these drugs. Quality control is an essential operation of the pharmaceutical industry, which also concerns analyses of finished dosage forms to determine compliance with label claims for active ingredients. Benzodiazepines are a type of psychotropic drug, in the sense that they concern the mind and can amend the frame of mind. The widespread use of this class of drugs has occasionally raised concern about recreational benzodiazepine abuse and has led to

Figure 6. Structural formulas of the benzodiazepines exploited to verify the applicability limits of the proposed determination method. E


Article

Inorganic Chemistry Table 3. Determination of Benzodiazepines in Pharmaceutical Preparations sample

claimed (mg)

found (%)

olanzapine (tablets) flurazepam (capsules) triazolam (tablets) diazepam (tablets) bromazepam (capsules)

20 30 0.25 5 6

100.1 ± 0.5 99.1 ± 1.2 95.8 ± 5.3 undetectable undetectable

We provided a reliable estimation of the above benzodiazepine pKa values by measuring the equilibrium constants for the processes

Figure 8. Free energy relationship between the equilibrium constants, at 298 K, of the reaction between some nitrogen bases and HCl in chloroform (pKc) vs water (pKa). Empty circles refer to substituted pyridines.

BZD + [(HR 2DTO)Pt(H 2R 2DTO)]+ [Cl−]

Table 4. pKa Values of Bases at 298 K

⇌ BZD·HCl + [Pt(HR 2DTO)2 ] R = benzyl, BZD = bromazepam, diazepam

The determined pKc values are related to the pKa values of the benzodiazepines under examination according to a suitable free energy relationship already found.15 pKa values of either BZDs or other low-basicity nitrogen compounds (aniline, 2,2′bipyridine, bromazepam, diazepam, triazolam) determined in chloroform (Figure 8 and Table 4) can be considered reliable, since these values do not significantly differ from those found in the literature,49−53 which have been determined in water or mixed solvents. As the equilibrium data of benzodiazepines are important in describing and understanding their mechanism of action,54 the possibility to evaluate pKa values of such substances from the corresponding pKc value measured in chloroform is very useful, since the extremely low solubility of BZDs in water poses severe limitations on their determination. Flurazepam bears on the N1 nitrogen a 2-(diethylamino)ethyl group as a substituent group, which is basic, like a generic tertiary alkylamine. Flurazepam is marketed as commercial tablets containing amine hydrochloride. For this reason, after extraction from tablets, the benzodiazepine hydrochloride needs to be dehydrohalogenated before titration. Then flurazepam as a free base has been determined with high accuracy and sensitivity (Figure 9). A similar result has been obtained by determining olanzapine, which is a well-known second-generation antipsychotic.

basic compound

pKaa

pKcb

pKac

3-chloropyridine 5-bromo-2-methylpyridine pyridine 3-methylpyridine 2.6-dimethylpyridine 2,2′-bipyridine aniline triazolam diazepam bromazepam

2.9 3.86 5.17 5.63 6.65 4.33 4.64 4.32 3.7 3

1.75 0.92* −0.3345 −0.9628 −2.6972 0.22* −0.01* −0.04* 0.98* 1.7*

4.42 4.62 4.65 3.76 3.13

a

pKa values from databases determined in water or mixed solvents. pKc values determined in CHCl3 by the authors (those marked with asterisks refer to this work). cpKa values extrapolated from the straight line in Figure 8 (see text): these values determined in CHCl3 are in a close agreement with those measured in water or mixed solvents. b

The results show that only BZDs which containing an alkylamine group in their molecular skeleton can be determined with high precision and sensitivity. Unfortunately, alkylamine substituents are contained only in a few BZDs which, in the great majority, show pKa values of less than 5; then, some of them can be determined with poor accuracy (Figure 7a), while the others cannot be determined at all by using the proposed method (Figure 7b,c). It will be probably be possible to carry out the spectrophotometric determination of benzodiazepines with pKa values beyond this

Figure 7. Titration curve of triazolam (a), diazepam (b), and bromazepam (c). F


Inorganic Chemistry

Article

■

EXPERIMENTAL SECTION

■

ASSOCIATED CONTENT

Reagents. Reagents were commercial products. Most of them were used as purchased. Chloroform, RS grade, was purified according to standard procedures.61 Secondary dithiooxamides62 and cis-Pt(Me2SO)2Cl263 were prepared according to the literature methods. The complexes [(H-R2DTO)Pt(H2-R2-DTO)][Cl] (II) and [(H-R-DTO)2Pt] (III) were prepared as previously reported.14 Benzodiazepines were purchased as tablets and capsules from local suppliers. In order to extract the active principle from pharmaceutical dosage forms, a number of capsules or tablets corresponding to 30 mg of active principle, deprived of their protective coating when necessary, were ground in a mortar. The resulting powder was stirred with 5 mL of chloroform at room temperature for 1 h; the sample solution was filtered using a sintered-glass filter, and the residue underwent the same treatment twice more. All of the extraction fractions were collected in a 25 mL flask, and the final volume was adjusted with chloroform. The extraction of flurazepam from flunox was made in the presence of a large excess of potassium carbonate. Instruments. Electronic spectra were recorded with a PerkinElmer Lambda 35 UV−vis spectrometer. 1H NMR and 13C{1H} NMR spectra were recorded at 298 K on a Bruker ARX-300 spectrometer, equipped with a broad-band probe operating at 300.13 and 75.56 MHz, respectively. Chemical shifts (δ, ppm) were referenced to SiMe4. Titration Procedures. Starting from weighed amounts of amines, stock solutions 1 × 10−3 mol dm−3 in chloroform have been obtained. At least 100 μL of each of them was pipetted into a standard spectrophotometric cuvette (1 cm optical path) and then diluted to 2 mL. The complexes [(HR2DTO)Pt(H2R2DTO)][Cl] (R = ethyl, 1; R = benzyl, 2), used as titrants, have been prepared according to reported procedures.14 The mother solutions of 1 and 2 were prepared by using weighed amounts of complexes; titrant solutions have been prepared by proper dilution of mother solutions (the typical platinum concentration ranged from 4 × 10−4 to 8 × 10−4 mol dm−3). In all experiments, the concentrations of the titrant solutions were checked by their molar absorptivities at 513 nm (1.15 × 104 mol−1 dm3 cm−1). An example of a titration plot is given as an Excel file in the Supporting Information. Determination of Equilibrium Constants. Solutions of complex II (8 × 10−5 to 1 × 10−4 mol dm−3) were prepared upon dilution of a 1 × 10−3 mol dm−3 mother solution prepared by weighing. The chloroform solution of the titrant was determined by weighing the proper nitrogen base (see Results and Discussion). All titrations were carried out by maintaining constant the total concentration of Pt. Each determination was performed by adding small and increasing portions of the proper quantity of the titrant to 2.0 cm3 of a 8 × 10−5 to 1 × 10−4 mol dm−3 solution of [(H-Et2-DTO)Pt(H2-Et2-DTO)][Cl] (II), placed in a spectrophotometric cuvette by means of a micropipet. Data analysis of equilibrium constant was performed with the program MicroMath Scientist.

Figure 9. Titration curve of flurazepam.

limiting pKa by exploiting more acidic titrant complexes, not yet at our disposal. Studies in such a direction will be performed in due course.

■

CONCLUDING REMARKS This paper has clearly shown that aliphatic amines can be determined in chloroform in a friendly, time-saving, highly reliable, and accurate titration procedure based on selfindicating inorganic complexes behaving as acidic species. Furthermore, the titrated sample can be recovered after determination, since amines do not need derivatization procedures and can be easily separated from the titrant by column chromatography. Thus, the proposed method of amine determination seems to be a particularly valuable tool in pharmaceutical analysis, since process monitoring and control are necessary at all stages of pharmaceutical processing, from raw material to packaged product characterization. Traditional quality control methods (high performance liquid chromatography and mass spectroscopy) are time-consuming, destructive, and expensive. In order to achieve low-cost analysis, spectrophotometric methods have been applied to amine determination in dosage forms.25,55−60 From a rapid comparison of the active principles determination reported in the quoted papers with the method adopted here for the determination of flurazepam in capsules, the noteworthy advantages of amine titration performed with self-indicating titrant complexes immediately appear clear. Furthermore, the amine determination method proposed here could be automated, without particular difficulties; this could be a further advantage in pharmaceutical processing because many samples of drugs may be tested from a given production batch. The method proposed here is suitable also for the determination of active principles, generally amphetamines, exploited for the illegal production of pills used as recreation drugs: as such, the method could also be of great interest for forensic chemistry. Eventually, the determination of biogenic amines extracted by biological matrices (blood, urines, tissues, foods, beverages) by means of self-indicating [Pt(HR2DTO)(H2R2DTO)][Cl] titrants will require a large number of experiments aimed at setting up suitable extraction procedures. In fact, the method requires neither amine derivatization nor formation of colored ion pairs. This fact makes it superfluous to check conditions which either ensure the stability of the colored derivatives or determine the interference of anions different from those providing the colored ion pair.

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b03081.

■

Example of a titration plot (XLSX)

AUTHOR INFORMATION

Corresponding Author

*E-mail for A.G.: [email protected]. ORCID

Antonino Giannetto: 0000-0002-6966-6113 Notes

The authors declare no competing financial interest. G


Article

Inorganic Chemistry

■

(20) López-Muñoz, F.; Alamo, C. Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from 1950s Until Today. Curr. Pharm. Des. 2009, 15, 1563−1586. (21) Westover, A. N.; McBride, S.; Haley, R. W. Stroke in Young Adults Who Abuse Amphetamines or Cocaine. A Population-Based Study of Hospitalized Patients. Arch. Gen. Psychiatry 2007, 64, 495− 502. (22) Perera, F. P. Environment and Cancer: Who Are Susceptible? Science 1997, 278, 1068−1073. (23) Pinheiro, H. M.; Touraud, E.; Thomas, O. Aromatic amines from azo dye reduction: status review with emphasis on direct UV spectrophotometric detection in textile industry wastewaters. Dyes Pigm. 2004, 61, 121−139. (24) Bartos, J. Sur une colorimétrie des alcoylamines, guanidines et ammoniums quaternaires par la réaction de janovsky. Talanta 1969, 16, 551−553. (25) Rizk, M. S.; Toubar, S. S.; Sultan, M. A.; Assaad, S. H. Ultraviolet Spectrophotometric Determination of Primary AmineContaining Drugs via Their Charge-Transfer Complexes with Tetracyanoethylene. Microchim. Acta 2003, 143, 281−285. (26) Vishnoi, P.; Sen, S.; Patwari, G. N.; Murugavel, R. Charge transfer aided selective sensing and capture of picric acid by triphenylbenzenes. New J. Chem. 2015, 39, 886−889. (27) Rizk, M. S.; Walash, M. I.; lbrahim, F. A. Spectrophotometric determination of piperazine via charge-transfer complexes. Analyst 1981, 106, 1163−1167. (28) Smith, R. E.; Davis, W. R. Spectrophotometric Determination of Amines with p-Chloranil. Anal. Chem. 1984, 56, 2345−2349. (29) Yamamoto, K. Sensitive determination of quaternary ammonium salts by extraction-spectrophotometry of ion associates with bromophenol blue anion and coextraction. Anal. Chim. Acta 1995, 302 (1), 75−79. (30) Mohammad, H. Y.; Cantwell, F. F. Photometric on-Pair Titrations in the Presence of an Immiscible Solvent and Their Application to Drug Analysis. Anal. Chem. 1979, 51, 1006−1012. (31) Omara, H. A.; Amin, A. S. Extractive-Spectrophotometric Methods for Determination of Alzheimer’s Drug in Pharmaceutical Formulations and in Biological Samples Using Sulphonphthalein Acid Dyes. Canadian Chemical Transactions 2016, 4, 17−31. (32) Umbreit, G. R. Spectrophotometric Determination of Secondary Amines. Anal. Chem. 1961, 33, 1572−1573. (33) Rawat, J. P.; Singh, J. P. Sensitive method for spectrophotometric determination of amines. Anal. Chem. 1975, 47, 738−741. (34) Harlow, G. A.; Morman, D. H. Titrations in nonaqueous solvents. Anal. Chem. 1968, 40, 418−428. (35) Biswas, H. K.; Mandal, B. M. Extraction of Anions into Chloroform by Surfactant Cations. Relevance to Dye Extraction Method of Analysis of Long Chain Amines. Anal. Chem. 1972, 44, 1636−1640. (36) Ö nal, A. A review: Current analytical methods for the determination of biogenic amines in foods. Food Chem. 2007, 103, 1475−1486. (37) “International Union of Pure and Applied Chemistry, Analitycal Chemistry Division, Commission on Analytical Reactions and Reagents”. Spectrophotometric and fluorimetric determination of amines. Pure Appl. Chem. 1984, 56, 467−477. (38) British Pharmachopoeia; Her Majesty’s Stationery Office: London, 1993; Vols. I and II. (39) Sugimura, T.; Wakabayashi, K.; Nakagama, H.; Nagao, M. Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish. Cancer Sci. 2004, 95, 290−299. (40) Lang, N. P.; Butler, M. A.; Massengill, J.; Lawson, M.; Graig Stotts, R.; Hauer-Jensen, M.; Kadlubar, F. F. Rapid Metabolic Phenotypes for Acetyltransferase and Cytochrome P4501A2 and Putative Exposure to Food-borne Heterocyclic Amines Increase the Risk for Colorectal Cancer or Polyps. Cancer Epidemiol., Biomarkers Prev. 1994, 3, 675−682. (41) Skog, K. I.; Johansson, M. A. E.; Jagerstad, M. I. Carcinogenic Heterocyclic Amines in Model Systems and Cooked Foods: A Review

ACKNOWLEDGMENTS Financial support from the Ministero dell’Università e della Ricerca (MIUR; FIRB project RBAP11C58Y Nanosolar, PRIN 2010-2011 Hi-Phuture) is gratefully acknowledged.

■

REFERENCES

(1) Park, C. H.; Simmonds, H. E. Macrobicyclic Amines. 111. Encapsulation of Halide Ions by in,in-l,(k + 2)-Diazabicyclo[k.l.m]alkane-ammonium Ions. J. Am. Chem. Soc. 1968, 90, 2431−2432. (2) Schmidtchen, F. P. Macrotricyclic Quaternary Ammonium Salts: Enzyme-Analogous Activity. Angew. Chem., Int. Ed. Engl. 1981, 20, 466−468. (3) Schmidtchen, F. P. Hosting anions. The energetic perspective. Chem. Soc. Rev. 2010, 39, 3916−3935. (4) Lehn, J. M. Supramolecular ChemistryScope and Perspectives Molecules, Supermolecules, and Molecular Devices (Nobel Lecture). Angew. Chem., Int. Ed. Engl. 1988, 27, 89−112 and references therein. (5) Bianchi, A.; Bowman-James, K.; Garcia-Espana, E. Supramolecular Chemistry of Anions; Wiley-VCH: New York, 1997,. (6) Schmidtchen, F. B.; Berger, M. Artificial Organic Host Molecules for Anions. Chem. Rev. 1997, 97, 1609−1646. (7) Kang, S. O.; Begum, R. A.; Bowman-James, K. Amide-Based Ligands for Anion Coordination. Angew. Chem., Int. Ed. 2006, 45, 7882−7894. (8) Li, A. F.; Wang, J. H.; Wang, F.; Jiang, Y. B. Anion complexation and sensing using modified urea and thiourea-based receptors. Chem. Soc. Rev. 2010, 39, 3729−3745. (9) Amendola, V.; Fabbrizzi, L. Anion receptors that contain metals as structural units. Chem. Commun. 2009, 513−531. (10) Fabbrizzi, L.; Poggi, A. Anion recognition by coordinative interactions: metal-amine complexes as receptors. Chem. Soc. Rev. 2013, 42, 1681−1699. (11) Amendola, V.; Fabbrizzi, L.; Mosca, L. Anion recognition by hydrogen bonding: urea-based receptors. Chem. Soc. Rev. 2010, 39, 3889−3915. (12) Mercer, D. J.; Loeb, S. J. Metal-based anion receptors: an application of second-sphere coordination. Chem. Soc. Rev. 2010, 39, 3612−3620. (13) Arion, V. B.; Beer, P. D.; Drew, M. G. B.; Hopkins, P. Anion recognition by nickel(II) and cobalt(III) complexes with quadridentate ligands based on isothiosemicarbazide. Polyhedron 1998, 18, 451−458. (14) Giannetto, A.; Puntoriero, F.; Barattucci, A.; Lanza, S.; Campagna, S. Tight-Contact Ion Pairs Involving Pt(II) Dithiooxamide Complexes: the Acid−Base Reactions between Hydrohalogenated IonPaired Complexes and Pyridine. Inorg. Chem. 2009, 48, 10397−10404. (15) Ielo, I.; Lanza, S.; Campagna, S.; Giannetto, A. The Reversible Formation of Tight Ion Pairs within Platinum(II) Complexes − A Study of Thermodynamic Parameters Governing Noncovalent Interactions. Eur. J. Inorg. Chem. 2016, 2016, 281−287. (16) (a) Shirhatti, P. R.; Maity, D. K.; Wategaonkar, S. C−H···Y Hydrogen Bonds in the Complexes of p-Cresol and p-Cyanophenol with Fluoroform and Chloroform. J. Phys. Chem. A 2013, 117, 2307− 2316. (b) Delanoye, S. N.; Herrebout, W. A.; van der Veken, B. J. Improper or Classical Hydrogen Bonding? A Comparative Cryosolutions Infrared Study of the Complexes of HCClF2, HCCl2F, and HCCl3 with Dimethyl Ether. J. Am. Chem. Soc. 2002, 124, 7490−7498. (17) Metrangolo, P.; Meyer, F.; Pilati, T.; Resnati, G.; Terraneo, G. Halogen Bonding in Supramolecular Chemistry. Angew. Chem., Int. Ed. 2008, 47, 6114−6127. (18) Gushchin, P. V.; Starova, G. L.; Haukka, M.; Kuznetsov, M. L.; Heremenko, I. L.; Kukushkin, V. Y. Chloride−Chloroform Clusters Exhibiting Weak Hydrogen and Halogen Bondings Are Fully Characterized in the Solid State by X-ray Diffraction. Cryst. Growth Des. 2010, 10, 4839−4846. (19) Santos, M. H. S. Biogenic amines: their importance in foods. Int. J. Food Microbiol. 1996, 29, 213−231. H


Article

Inorganic Chemistry on Formation, Occurrence and Intake. Food Chem. Toxicol. 1998, 36, 879−896. (42) Knize, M. G.; Felton, J. S. Formation and Human Risk of Carcinogenic Heterocyclic Amines Formed from Natural Precursors in Meat. Nutr. Rev. 2005, 63, 158−165. (43) Barrett, J.; Franklin Smyth, W.; Davidson, I. E. An examination of acid-base equilibria of 1,4-benzodiazepines by spectrophotometry. J. Pharm. Pharmacol. 1973, 25, 387−393. (44) Clifford, J. M.; Franklin Smyth, W. The determination of some 1,4-benzodiazepines and their metabolites in body fluids. A review. Analyst 1974, 99, 241−271. (45) Davidson, A. G. Difference spectrophotometric assay of nitrazepam in tablet formulations. J. Pharm. Pharmacol. 1989, 41, 63−65. (46) Sánchez Rojas, F.; Bosch Ojeda, C. Recent development in derivative ultraviolet/visible absorption spectrophotometry: 2004− 2008: A review. Anal. Chim. Acta 2009, 635, 22−44. (47) Sadeghi, S.; Takjoo, R.; Haghgoo, S. Quantitative Determination of Diazepam in Pharmaceutical Preparation by Using a New Extractive-Spectrophotometric Method. Anal. Lett. 2002, 35, 2119− 2131. (48) Fukumoto, M. Spectrophotometric Determination of Bromazepam. Chem. Pharm. Bull. 1980, 28, 3678−3681. (49) Bayes, G. S.; Lakshmi Narasimham, Y. S.; Raut, S. S.; Patil, V. R.; Lokhande, R. S. Automated Potentiometric Titration Method for Determination of pK Values: An Application to Benzodiazepines. J. Chem. Eng. Data 2011, 56, 1787−1792. (50) Barbosa, J.; Sanz-Nebot, V. Existence of two basic sites in triazolo-1,4-diazepines: determination of two pKa values for a model compound in water. Talanta 1989, 36, 837−842. (51) Legouin, B.; Burgot, J. Existence of two basic sites in triazolo1,4-diazepines: determination of two pKa values for a model compound in water. Analyst 1996, 121, 43−48. (52) Yang, S. K. J. Acid-base Equilibria of 1,4-Benzodiazepine 4Oxides by Spectrophotometry. J. Pharm. Pharmacol. 1995, 47, 442− 447. (53) Pfendt, L. B.; Sladic, D. M.; Janjic, T. J. Study of heterogeneous equilibria in saturated aqueous solutions of some 7-chloro-1,4benzodiazepines. Analyst 1990, 115, 383−387. (54) Fischer, J. B.; Olsen, R. W. In Benzodiazepines/GABA Receptors and Chloride Channels: Structural and Functional Properties; Olsen, R. W., Venter, J. C., Eds.; Liss: New York, 1986; Receptor Biochemistry and Methodology, Vol. 51, pp 241−259. (55) Al-Ghannam, S. M. A simple spectrophotometric method for the determination of β-blockers in dosage forms. J. Pharm. Biomed. Anal. 2006, 40, 151−156. (56) Elbashir, A. A.; Suliman, F. E. O.; Aboul-Enein, H. Y. The Application of 7-Chloro-4-nitrobenzoxadiazole (NBD-Cl) for the Analysis of Pharmaceutical-Bearing Amine Group Using Spectrophotometry and Spectrofluorimetry Techniques. Appl. Spectrosc. Rev. 2011, 46, 222−241. (57) Kuwabara, T.; Nakajima, H.; Nanasawa, M.; Ueno, A. Color Change Indicators for Molecules Using Methyl Red-Modified Cyclodextrins. Anal. Chem. 1999, 71, 2844−2849. (58) Martin, M. A.; del Castillo, B. 2,3-Diphenylquinolizinium bromide as a fluorescent derivatization reagent for amines. Anal. Chim. Acta 1991, 245, 217−223. (59) Mustafa, A. A.; Abdel-Fattah, S. A.; Toubar, S. S.; M, A. Spectrophotometric Determination of Acyclovir and Amantadine Hydrochloride through Metals Complexation. Sultan. J. Anal. Chem. 2004, 59, 33−38. (60) El-Bagary, R. I.; Elkady, E. F.; Ayoub, B. M. Spectrophotometric Methods for the Determination of Sitagliptin and Vildagliptin in Bulk and Dosage Forms. Int. J. Biomed Sci. 2011, 7, 55−61. (61) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals; Butterworth-Heinemann: London, 2003. (62) Hurd, R. N.; De La Mater, G.; McElheny, C. G.; Turner, R. J.; Vallingford, V. H. Preparation of dithiooxamide derivatives. J. Org. Chem. 1961, 26, 3980−3987.

(63) Kukushkin, Y. N.; Viaz’menskii, Y. E.; Zorina, L. I. Complexes of palladium and platinum with dimethyl sulfoxide. Russ. J. Inorg. Chem. 1968, 13, 835−838.

I


Metal Complexes as Self-Indicating Titrants for ... - ACS Publications

Recommend Documents