Synthesis of 3-alkyl-1,2,3-triazol-1-ium hydrogen sulphate derivatives

Abstract

An array of 3-alkyl-1,2,3-triazol-1-ium hydrogen sulphate derivatives was obtained from the reaction between some 1,4-disubstituted-1,2,3-triazoles and H₂SO₄ through a simple protocol in good yields. The molecular structure of a triazolium salt (R¹ = PhCH₂, R² = CH₂O(4-CHO)C₆H₄) was unambiguously determined from X-ray diffraction studies, showing a remarkable triazole N3–H bond.

Keywords

1,2,3-triazole crystal structure CuAAC reaction protonation triazolium salt

Introduction

1,2,3-Triazolium salts are a promising class of molecules due to their growing number of uses as ionic liquids as well as metal ligands for catalysis.^1-5 Nonetheless, the structural diversity presented by 1,2,3-triazolium salts is rather limited as a consequence of the few methods available for the preparation of these compounds which are based on methylation and arylation at the triazole N3 nitrogen,⁶ as well as cycloadditions between 1,3-diaza-2-azoniaallene salts and alkynes.⁷ This constraint is attributed to the low basicity/nucleophilicity of 1,2,3-triazole compared to other heterocycles.^8,9 Moreover, there are only a few examples of N–H 1,2,3-triazolium salts reported in literature. Drake and coworkers reported the formation of unsubstituted 1,2,3-triazole nitrate and perchlorate.¹⁰ However, substituted 1,2,3-triazoles have not been studied.

Despite these serious drawbacks, the idea of the synthesis of 1,2,3-triazolium salts from 1,2,3-triazoles is still attractive due to their high availability provided by the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and click chemistry approaches.¹¹ Hence, we decided to investigate the formation of 1,2,3-triazolium salts from simple protonation reactions.

Thus, an array of 1,2,3-triazoles prepared by our group^12,13 through CuAAC reactions was used in this study. Initial experiments with hydrohalic acids afforded no evidence about 1,2,3-triazolium salt formation. On the other hand, straightforward treatment of diverse 1,2,3-triazoles with H₂SO₄ gave the corresponding 1,2,3-triazolium hydrogen sulphate derivatives 1–8 in 72%–98% yields (Scheme1, Table 1). Triazolium salts 1–8 are stable compounds at ambient temperatures up to 30 °C, not hygroscopic, insoluble in water but in most cases soluble in polar solvents as methanol, acetone and dimethyl sulfoxide among others. Although pKa/acidity for N3–H was not determined, the value of this parameter could be close to other similar acidic azolium salts,^14,15 representing a challenging task for future investigations.

Table 1.

Synthesis of 1,2,3-triazolium hydrogen sulphate derivatives.

Compound	R¹	R²	% Yield
1	PhCH₂	CH₂O(4-Cl)C₆H₄	80
2	PhCH₂	CH₂O(4-CH₃)C₆H₄	72
3	PhCH₂	CH₂O(4-CHO)C₆H₄	98
4	4-CH₃OC₆H₄	Ph	81
5	4-NO₂C₆H₄	Ph	65
6	4-ClC₆H₄	Ph	77
7		CH₂O(4-Br)C₆H₄	83
8		CH₂O(4-COCH₃)C₆H₄	89

Scheme 1.

Synthesis of 1,2,3-triazolium hydrogen sulphate derivatives from 1,2,3-triazoles.

1,2,3-Triazolium hydrogen sulphate derivatives 1–8 were characterized by conventional spectroscopic techniques and compound 3 was a crystalline solid which was studied by X-ray crystallography. Crystallographic data and structural refinement parameters of compound 3 are summarized in Table 2. From single-crystal X-ray diffraction analysis, the crystal structure of 3 presents a noteworthy N–H bond with a distance between triazole N3 nitrogen and hydrogen atoms, N3–H = 0.869 Å and angles H3–N3–N2 (119.07°), H3–N3–C2 (127.79°) and N2–N3–C2 (112.98°). These features not only corroborate the triazolium salt formation and the proposed structure for this compound but also show a reactivity pattern and indicate selective protonation of the N3 position of the 1,2,3-triazole ring (Figure 1). Selected bond distances and angles are given in Table 3 and are shown in Figure 2.

Table 2.

Crystal data and structure refinement of X-ray diffraction for compound 3.

Crystal data	3
Empirical formula	C₁₇H_18.84N₃O_6.92S
Formula weight	407.99
Temperature (K)	100(2)
Wavelength (Å)	0.71073
Crystal system	Monoclinic
Space group	P 2₁/n
Unit cell dimensions (Ǻ, °)
a	16.8056(8)
b	6.9227(3)
c	17.4153(8)
α	90
β	114.4582(8)
γ	90
Volume (Ǻ³)	1844.28(15)
Z	4
Calculated density D (mg m⁻³)	1.469
F(000)	853
Absorption coefficient µ (mm⁻¹)	0.222
Crystal size (mm³)	0.337 × 0.232 × 0.231
θ_max(º)	27.446
θ_min(º)	2.200
h	−21→21
k	−8→8
l	−22→22
Reflections collected	19,451
Independent reflection	4198 (R(int) = 0.0224)
Data/restraints/parameters	4198 / 237 / 314
Goodness-of-fit on F²	1.038
Final R indices (I> 2σ (I))	R¹ = 0.0397, wR² = 0.1046
R indices (all data)	R¹ = 0.0427, wR² = 0.1069

Table 3.

Selected bond distances (Å) and bond angles (°) for 3-benzyl-5-(4-formylphenoxymethyl)-1,2,3-triazol-1-ium hydrogen sulphate 3, C₁₇H₁₇N₃O₆S.

Bond	Distance (Å)	Bond	Angle (°)
N(1)–N(2)	1.3229(17)	N(2)–N(1)–C(1)	112.91(12)
N(1)–C(1)	1.3510(18)	N(3)–N(2)–N(1)	103.68(11)
N(2)–N(3)	1.3209(17)	N(2)–N(3)–C(2)	112.99(12)
N(3)–C(2)	1.3539(18)	N(2)–N(3)–H(3)	119.1(13)
N(3)–H(3)	0.869(9)	C(2)–N(3)–H(3)	127.8(13)
C(1)–C(2)	1.369(2)	N(1)–C(1)–C(2)	105.34(12)
C(1)–H(1)	0.9500	N(1)–C(1)–H(1)	127.3

Figure 1.

ORTEP diagram and atom labelling system for compound 3.

Figure 2.

Molecular structure of 3 showing N(3)–H(3) distance and angle N(2)–N(3)–H(3).

The compounds shown herein represent the first substituted 1,2,3-triazolium salts as well as the earliest examples of 1,2,3-triazolium salts containing a hydrogen sulphate anion. These facts are important because they demonstrate that 1,2,3-triazoles derived from CuAAC reactions are susceptible of being converted into 3-substituted 1,2,3-triazol-1-ium salts by a mild and simple methodology. In addition, interesting applications are envisioned for these compounds. For instance, in medicinal chemistry, triazolium salts are worthy of investigation as anticancer agents¹⁶ and could play a relevant role in the delivery of antifungal compounds by enhancing the solubility and biological activity of some azolium salts compared to other azole antifungal drugs.^17,18

In brief, 3-alkyl-1,2,3-triazol-1-ium hydrogen sulphate derivatives are readily synthesized from 1,4-disubstituted-1,2,3-triazoles which in turn are prepared from CuAAC reactions through a facile synthetic protocol which allows a fast access to this class of compounds which will increase the research in this area. The simplicity of the method suggests that this route to 3-alkyl-1,2,3-triazol-1-ium hydrogen sulphate derivatives will enjoy widespread application.

Experimental

General remarks

The starting materials were purchased from Aldrich Chemical Co. and were used without further purification. Solvents were distilled before use. Silica plates of 0.20-mm thickness were used for thin-layer chromatography. Melting points were determined with a Krüss Optronic melting point apparatus and they are uncorrected. 1H and 13C NMR spectra were recorded using a Bruker Avance 300 MHz, and a Varian 500 MHz; the chemical shifts (δ) are given in ppm relative to tetramethylsilane (TMS) as an internal standard (0.00). For analytical purposes, the mass spectra were recorded on a Shimadzu GCMS-QP2010 Plus in the EI mode, 70 eV, 200 °C via direct inlet probe. Only the molecular and parent ions (m/z) are reported. Infrared (IR) spectra were recorded on a Bruker TENSOR 27 FT instrument. 1,2,3-triazoles were prepared according to the literature.^12,13

For the X-ray diffraction studies, crystals of compound 3 were obtained by slow evaporation of a dilute MeOH solution, and the reflections were acquired with a Bruker APEX DUO diffractometer equipped with an Apex II charge-coupled device (CCD) detector. Three standard reflections every 97 reflections were used to monitor the crystal stability. The structures were solved by direct methods; missing atoms were found by difference Fourier synthesis, and refined on F2 by a full-matrix least-squares procedure using anisotropic displacement parameters using SHELX-97. Crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre (CCDC; No. 2043876 for compound 3). Copies of available materials can be obtained free of charge on application to the Director, CCDC, 12 Union Road, Cambridge CB2 IEZ, UK (facsimile: (44) 01223 336033); e-mail: deposit@ccdc.

Synthesis of 3-alkyl-1,2,3-triazol-1-ium hydrogen sulphate derivatives

Typical procedure: 98% H₂SO₄ (0.03 mL) was added to a solution of the appropriate 1,2,3-triazole (0.10 g) in CH₂Cl₂ (2 mL) at room temperature. The resulting reaction mixture was gently stirred at room temperature for 1 min, and the precipitate was collected by filtration, washed successively with cold ether and CH₂Cl₂ and dried under reduced pressure to afford the corresponding 3-alkyl-1,2,3-triazol-1-ium hydrogen sulphate derivative which was purified by crystallization (MeOH).

3-Benzyl-5-(4-chlorophenoxymethyl)-1,2,3-triazol-1-ium hydrogen sulphate (1)

White solid, m.p. 69 °C (80%). IR (ATR, cm⁻¹): 3160, 3000, 1590, 1450, 1443. 1H NMR (300 MHz, DMSO-d₆): δ 7.33–7.34, (m, 2H), 7.29 (s, 1H), 7.28 (m, 4H), 7.04, (m, 2H), 5.60, (s, 2H), 5.11 (s, 2H). 13C NMR (75 MHz, DMSO-d₆): δ 157.0, 142.8, 136.09, 129.4, 128.9, 128.3, 128.1, 125.0, 116.7, 61.5, 53.0. Anal. calcd. for C₁₆H₁₆ClN₃O₅S (%): C 48.30, H 4.05, N 10.56; found: C 48.35, H 4.13, N 10.50.

3-Benzyl-5-(p-tolyloxymethyl)-1,2,3-triazol-1-ium hydrogen sulphate (2)

White solid, m.p. 78 °C (72%). IR (ATR, cm⁻¹): 3440, 2880, 2160, 2030, 1680, 1153. 1H NMR (300 MHz, DMSO-d₆): δ 8.22 (s, 1H), 7.28 (m, 5H), 7.00, (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 5.54, (s, 2H), 5.01, (s, 2H), 2.15 (s, 3H). 13C NMR (75 MHz, DMSO-d₆): δ 156.5, 143.8, 136.5, 130.6, 130.4, 129.5, 129.0, 128.7, 125.5, 115.3, 61.5, 53.6, 20.7. Anal. calcd. for C₁₇H₁₉N₃O₅S (%): C 54.10, H 5.07, N 11.13; found: C 54.17, H 5.03, N 11.17.

3-Benzyl-5-(4-formylphenoxymethyl)-1,2,3-triazol-1-ium hydrogen sulphate (3)

White solid, m.p. 87 °C (98%). IR (ATR, cm⁻¹): 3355, 3145, 2352, 1748, 1600, 1582, 1510, 1450, 1400, 1300, 1250, 1200, 1150. 1H NMR (300 MHz, DMSO-d₆): δ 9.87, (s, 1H), 8.34, (s, 1H), 7.87, (d, J = 8.9 Hz, 2H), 7.40, (m, 5H), 7.25 (m, 2H), 5.61, (s, 2H), 5.26 (s, 2H). 13C NMR (75 MHz, DMSO-d₆): δ 191.5, 163.0, 136.0, 131.9, 129.9, 128.9, 128.3, 128.1, 125.29,1, 115.3, 61.5, 53.0. Anal. calcd. for C₁₇H₁₇N₃O₆S (%): C 52.17, H 4.38, N 10.74; found: C 52.14, H 4.33, N 10.79.

3-(4-Methoxyphenyl)-5-phenyl-1,2,3-triazol-1-ium hydrogen sulphate (4)

White solid, m.p. 55 °C (81%). IR (ATR, cm⁻¹): 3400, 3150, 2808, 1600, 1510, 1474, 1297, 1244, 1197. 1H NMR (300 MHz, DMSO-d₆): δ 9.19 (s, 1H), 7.95, (d, J = 9.2 Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H), 7.51 (m, 2H), 7.40 (m, 1H), 7.18 (m, 2H), 3.84 (s, 3H). 13C NMR (75 MHz, DMSO-d₆): δ 160.2, 148.6, 130.9, 130.2, 129.3, 128.7, 126.2, 122.8, 118.2, 115.3, 56.5. Anal. calcd. for C₁₅H₁₅N₃O₅S (%): C 51.57, H 4.33, N 12.03; found: C 51.54, H 4.38, N 12.08.

3-(4-Nitrophenyl)-5-phenyl-1,2,3-triazol-1-ium hydrogen sulphate (5)

White solid, m.p. 78 °C (65%). IR (ATR, cm⁻¹): 3400, 3156, 3120, 1600, 1523, 1480, 1357, 1232, 1197. 1H NMR (300 MHz, DMSO-d₆): δ 8.47, (d, J = 8.0 Hz, 2H), 8.3, (s, 1H), 7.94, (m, 2H), 7.67, (m, 2H), 7.41-7.57, (m, 3H). 13C NMR (75 MHz, DMSO-d₆): δ 148.3, 147.1, 141.3, 130.3, 129.5, 129.0, 128.5, 126.1, 125.9, 120.8, 120.4. Anal. calcd. for C₁₄H₁₂N₄O₆S (%): C 46.15, H 3.32, N 15.38; found: C 46.17, H 3.37, N 11.41.

3-(4-Chlorophenyl)-5-phenyl-1,2,3-triazol-1-ium hydrogen sulphate (6)

White solid, m.p. 154 °C (Dec.) (77%). IR (ATR, cm⁻¹): 3400, 3156, 3120, 1600, 1523, 1478, 1235. 1H NMR (300 MHz, DMSO-d₆): δ 9.35, (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.95, (d, J = 8.9 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.52 (m, 2H), 7.42 (m, 1H). 13C NMR (75 MHz, DMSO-d₆): δ 151.1, 137.9, 133.2, 131.3, 128.9, 128.2, 126.1, 126.1, 124.8, 122.3. Anal. calcd. for C₁₄H₁₂ClN₃O₄S (%): C 47.53, H 3.42, N 11.88; found: C 47.52, H 3.47, N 11.92.

5-(4-Bromophenoxymethyl)-3-(tetrahydrofuran-2-ylmethyl)-1,2,3-triazol-1-ium hydrogen sulphate (7)

White solid, m.p. 48 °C (83%). IR (ATR, cm⁻¹): 3400, 3150, 2996, 2900, 2350, 1900, 1670, 1497, 1450, 1293, 1152. 1H NMR (300 MHz, DMSO-d₆): δ 8.08, (s, 1H), 7.37, (d, J = 8.9 Hz, 2H), 6.95, (d, J = 8.9 Hz, 2H), 5.04, (s, 2H), 4.41, (m, 2H), 4.31, (dd, J = 9.0, 4.5 Hz, 1H), 3.62, (m 2H), 2.50, (m, 1H), 1.92, (m, 1H), 1.74, (m, 2H), 1.52 (m, 1H). 13C NMR (75 MHz, DMSO-d₆): δ 158.0, 142.9, 133.0, 126.3, 118.0, 113.1, 77.5, 68.3, 61.8, 54.1, 28.9, 25.7. Anal. calcd. for C₁₄H₁₈BrN₃O₆S (%): C 38.54, H 4.16, N 9.63; found: C 38.59, H 4.14, N 9.69.

5-(4-Acetylphenoxymethyl)-3-(tetrahydrofuran-2-ylmethyl)-1,2,3-triazol-1-ium hydrogen sulphate (8)

White solid, m.p. 64 °C (89%). IR (ATR, cm⁻¹): 3400, 3157, 2913, 2400, 1920, 1708, 1600, 1587, 1482, 1276, 1211, 1163, 1158. 1H NMR (300 MHz, DMSO-d₆): δ 8.13, (s, 1H), 7.80, (d, J = 9.2 Hz, 2H), 7.14, (d, J = 9.1 Hz, 2H), 5.18, (s, 2H), 4.42, (dd, J = 7.5, 4.5 Hz, 1H), 4.31, (dd, J = 8.7, 4.2 Hz, 1H), 3.62, (m, 2H), 3.14, (m, 1H), 2.55 (s, 3H), 1.93 (m, 1H), 1.71, (m, 2H), 1.51 (m, 1H). 13C NMR (75 MHz, DMSO-d₆): δ 164.0, 142.8, 133.1, 130.9, 126.9, 116.4, 77.8, 68.6, 62.1, 62.1, 54.5, 29.2, 26.0. Anal. calcd. for C₁₆H₂₁N₃O₇S (%): C 48.11, H 5.30, N 10.52; found: C 48.17, H 5.36, N 10.55.

Footnotes

Acknowledgements

The authors would like to thank N. Zavala, A. Nuñez, L. Triana and M. C. Martínez for the technical support.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this paper.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this paper: Financial support was obtained from CONACYT (project No. A1-S-18230).

ORCID iD

Erick Cuevas-Yañez

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