Note pubs.acs.org/joc
Sulfur Groups Improve the Performance of Triazole- and TriazoliumBased Interaction Units in Anion Binding Mónica Á lvarez-Pérez,† Marina Velado,† Diego García-Puentes,† Elena Sáez,‡ Cristina Vicent,† Roberto Fernández de la Pradilla,†,∥ Alma Viso,*,†,∥ María C. de la Torre,†,∥ and Miguel A. Sierra*,§,∥ †
Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas (IQOG-CSIC), Juan de la Cierva 3, 28006-Madrid, Spain ‡ CAI de RMN y RSE, Universidad Complutense, 28040-Madrid, Spain § Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense, 28040-Madrid, Spain ∥ Centro de Innovación en Química Avanzada (ORFEO−CINQA), Madrid, Spain S Supporting Information *
ABSTRACT: An NMR comparative study of 1,2,3-triazole and triazolium anion recognition units containing sulfoxide, sulfone, and sulfoximine groups at C4 unveils an enhancement in binding ability up to ≈1 kcal/mol in acetone-d6 correlated with a theoretical increase of H5 acidity. DFT calculations provide insight into binding modes in line with experimental data for these receptors.
A
nions, critical to environmental1a and biological processes,1b have been the focus of attention in the development of a variety of receptors. Lately, an appreciation of systems bearing CH donor partners through a hydrogen bond (HB) has gained increasing attraction in the field of anion recognition.2 Among them and undoubtedly favored by the feasibility of the Cu(I)-catalyzed Huisgen azide−alkyne cycloaddition,3 1,2,3-triazoles are emerging as versatile scaffolds in supramolecular interactions.4 Their unexpected anion-binding affinities can be rationalized on the grounds of a highly polarized C5−H bond. In the related N-alkylated 1,2,3-triazoles (1,2,3-triazolium salts), the C5−H acidity is increased and the covalent contribution of the hydrogen bond is enhanced, although the hydrogen bonds are still mostly electrostatic in character.5a Most of the triazole and triazolium derivatives studied so far in anion recognition bear at least two units of the heterocycle or tend to be sophisticated molecules like foldamers,5 macrocycles,6 or interlocked architectures.7 Monomeric systems are scarce,8 even though cooperativity can be provided by including N−H donors close to the heterocycle9 or suitable aromatic substituents10 that work synergistically with the C5−H on complexing the anion. Because focusing on cooperative donor-donor systems has prevailed, studies on the effect of other substituents in anion binding have been limited. Only recently, a theoretical work comparing the effect of triazole/ triazolium C4 substituents on the binding ability to anions has been released.11,12 Additionally, the influence of groups at the para-position of cooperative aromatic substituents, directly linked to the C4 position of triazolium rings, has been noted.13 With the exception of thioureas14 and sulfonamides,15 anion receptors bearing sulfur-based functional groups are scarcely © XXXX American Chemical Society
documented. Recently, some receptors containing phenol and sulfinamide groups have been reported.16 However, in spite of the great interest in sulfur groups,17 sulfoxides, sulfones, and sulfoximines have not been considered in anion recognition probably because they would represent proton acceptors instead of proton donors.18 Here, we report the Cl− binding of triazole and triazolium rings having sulfoxide, sulfone, and sulfoximine groups (Figure 1). In order to minimize other contributions to binding and
Figure 1. Receptors evaluated for anion recognition in this study.
focus on the effect of the sulfur group, structurally simple recognition scaffolds were designed. Triazoles 1b−d were provided with a p-bromophenyl (pBrC6H4) fragment connected to the sulfur-based function that could facilitate the building of more complex receptors as well as assist in Received: February 2, 2017 Published: February 20, 2017 A
DOI: 10.1021/acs.joc.7b00261 J. Org. Chem. XXXX, XXX, XXX−XXX
Note
The Journal of Organic Chemistry Table 1. δH5 and δC5 Values (ppm) for the Free Receptors δH5a δC5b a
1a
1b
1c
1d
2a
2b
2c
2d
7.65 121.4
8.34 123.9
8.77 125.9
8.89 127.7
8.60 128.9
9.19 131.5
9.62 135.3a
9.80 134.5
In acetone-d6. bIn CDCl3.
in the splitting pattern of Hg, which progressively derived in an AB system after addition of 0.8 equiv of Cl−. Such an evolution of the signal shape supported the formation of a complex, conformationally more restricted than the receptor itself. Changes in the signal of H a were monitored for determination of association constants (KR:Cl, Table 2) by
monitoring changes in aromatic areas during titration experiments. Accordingly, sulfinyl triazole 1b was obtained by a recently described synthesis of chiral triazoles through a CuAAC reaction of acetylene sulfoxides and azides.19a Chemoselective sulfoxide oxidation (m-CPBA) provided sulfonyl triazole 1c and imination with PhINTs/Cu(OTf)2 gave sulfoximine 1d in excellent yield.19b Compound 1a,19c having a CH2 group, was considered for comparison on the grounds of ease and availability of starting materials. Further chemoselective Nmethylation afforded 2a−d in good yields.20 Remarkably, no secondary O-methylation was observed for the sulfinyl triazole. Initially, compounds 1a−d and 2a−d were evaluated by 1H and 13C NMR at constant concentration. The H5 proton of the triazole ring appeared as a sharp singlet with increasing δH5 values in the order CH2 < SO < SO2 < SONTs in each series (Table 1), in line with expected decreasing pKa values.21 In addition, a good correlation between δC5 values in CDCl3 and expected anion affinities occurred. We subsequently evaluated the anion recognition properties of the receptors toward tetrabutylammonium chloride (TBACl) by 1H NMR in acetone-d6. Upon addition of Cl−, both neutral and charged derivatives gave sharp signals and changes in chemical shifts corresponding to a fast interchange regime on the 1H NMR time scale. In contrast to prior studies,8a,13,22 the Cl− anion interacted with the compounds and induced measurable perturbations in the 1H NMR spectra. The signal of Ha (H5 of the triazole/triazolium ring) was the most deshielded in all the cases (Δδ = 0.39−1.37 ppm for neutral compounds, Δδ = 1.12−2.25 ppm for the charged ones). Apart from Ha, Hd and Hg (see Figure 2) underwent signal deshielding in all cases, suggesting their participation in HB to the Cl− anion. For some compounds, especially the methylated ones, the signal of Hb was also slightly shifted downfield (Δδ = 0.12−0.24 ppm). In the representative example of 2d, shown in Figure 2, we also observed a change
Table 2. Binding Constants and Experimental Binding Gibbs Energy Changes (kcal/mol) for Complexes R:Cl− Determined by 1H NMR Titrations (Acetone-d6, 298 K). Theoretical Interaction Energies (Eicalc) for Complexes Are Also Given (kcal/mol)b receptor, R 1a (CH2) 1b (SO) 1c (SO2) 1d (SONTs) 2a (CH2) 2b (SO) 2c (SO2) 2d (SONTs)
KR:Cl (M−1) 2 9 15 15 790 1600 3000 3940
± ± ± ± ± ± ± ±
1 1 1 1 60 50 300 40
ΔGexp −0.4 −1.3 −1.6 −1.6 −4.0 −4.4 −4.8 −4.9
± ± ± ± ± ± ± ±
0.3 0.2 0.1 0.1 0.1 0.1 0.1 0.1
Eicalc −3.2 −4.8 −3.8 n.c.a −6.5 −6.7 −7.6 −8.8
a
n.c.: not calculated. bErrors were calculated as standard deviations of duplicate titrations.
nonlinear regression analysis carried out using the Solver utility in Excel (see the SI). Best fits were achieved by considering a 1:1 binding model in all cases (Figure 3). The corresponding experimental Gibbs energy changes were determined in kcal/ mol from the KR:Cl values at 298 K (Table 2). A binding energy increment of ≈1 kcal/mol took place when a sulfur-based function was incorporated to the structure of the neutral receptors (1b−d vs 1a), while such an increment ranged between 0.4 and 1.0 kcal/mol for the methylated derivatives (2b−d vs 2a). When comparing 2b−d to the parent
Figure 3. Binding isotherms following Ha (H5) chemical shift, triazole (circles) and triazolium (triangles), under addition of TBACl in acetone-d6 at 298 K. 1a and 2a (black), 1b and 2b (red), 1c and 2c (green), and 1d and 2d (blue). Receptor concentration: 5 × 10−3 M (1a−1d) and 5 × 10−4 M (2a−2d).
Figure 2. 1H NMR spectra upon titration of 2d (5 × 10−4 M) with TBACl (0−14 equiv) in acetone-d6 at 298 K (400 MHz). B
DOI: 10.1021/acs.joc.7b00261 J. Org. Chem. XXXX, XXX, XXX−XXX
Note
The Journal of Organic Chemistry triazoles 1b−d, the ΔG value increased, as expected, between 3.1 and 3.3 kcal/mol. Even though the values of the association constant were small for the neutral triazoles, the analysis of the isotherms satisfyingly suggested a correlation between binding ability and expected pKa of Ha. Moreover, the increase in binding upon introduction of a sulfur-based group at C4 was equivalent to the effect of two aryl substituents at 1,4 positions of the triazole.8b The methylated derivatives 2b−2d have better binding abilities than other compounds which contained single7b,8c or bistriazolium rings,13 and not very different from triazolium monomers featuring an NH group for induction of cooperative interaction.23 In addition, we have considered CDCl3 as solvent for titration of our receptors with TBACl by NMR. However, the preliminary 1H NMR dilution experiments of the triazolium receptors (5 × 10−2 M, 5 × 10−3 M, 5 × 10−4 M, 10−4 M) have revealed not only pronounced changes in chemical shifts (H5, ArH, CH2) but also noticeable alterations in the couplings of the aromatic protons (see the SI, Figures S48 and S49). The above observations seem to indicate that aggregation of the receptors in the less polar halogenated solvent is taking place even at high dilution, and therefore, complexation in CDCl3 is expected to be far from the 1:1 models that we characterized in acetone-d6. In the same line, the TBACl ion-pairing effect could interfere in complexation since it has been observed in CH2Cl2.24 All the above made us cease in pursuing the study in CDCl3. In order to get additional information on the geometry of the receptors and on their binding mode to the Cl− anion, computational studies and 1D-NOE experiments were carried out. A model for a plausible 1b:Cl− complex in acetone was obtained at the m06/6-31+G(d,p) level of calculation including the solvent effect by the PCM method (Figure 4). According to the model, the distances describing the anion binding [d(Cl−− Ha) = 2.45 Å, d(Cl−−Hd) = 2.84 Å, d(Cl−−Hg) = 2.87 Å] were under the sum of the van der Waals radii of hydrogen and Cl−
(2.95 Å),8b and angles took typical values between 110° and 180° [a(C5−Ha···Cl−) = 154°, a(C−Hd···Cl−) = 155°, a(HC− Hg···Cl−) = 142°).25 Such a model also agreed with the observation of a positive NOE between Ha and Hb in the 1DNOE experiment performed on complex 1b:Cl− (d(Ha−Hb) = 3.62,
