Facile and High-Yielding Synthesis of TAM Biradicals and Monofunctional TAM Radicals

Abstract

Facile and high-yielding procedures for the synthesis of monocarboxylic acid derivatives of triarylmethyl radicals (TAM) were developed. Reaction of methyl thioglycolate with tris(2,3,5,6-tetrathiaaryl)methyl cation smoothly afforded the monosubstituted TAM derivative, which was hydrolyzed to a monocarboxylic acid, with the TAM moiety attached to thioglycolic acid via the sulfur atom. Alternatively, the diamagnetic tricarboxylic acid precursor of Finland trityl was transformed to a trimethyl ester and partially hydrolyzed under controlled conditions. The diester product was isolated, and the remaining fractions were converted back into the trimethyl ester for production of more diester. The first representatives of TAM biradicals with different TAM cores and interspin distances were obtained by reaction of these new TAM monocaboxylic acids with N,N′-dimethylethylenediamine.

Key words

free radicals - persistent triarylmethyls - TAM derivatives - spin labels - biradicals

• References

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• 10 In addition, the symmetrical TAM 3 may also result from direct single-electron reduction (ref. 9) of cation 1 by methyl thioglycolate.
• 11 Triarylmethanol – the precursor of cation 1 (Scheme 1) – is readily available in large scale (up to 10–20 g) and in high yield using the recently published protocol (Rogozhnikova et al.^8a).
• 12 Substitution of toluene with more polar solvents leads to a notable decrease in yield of TAM 2: 41% (CH₂Cl₂), 16–22% (Et₂O, THF), 12% (DMF).
• 13 LiOH as an alkaline reagent is strongly recommended: the use of NaOH or KOH resulted in poor yield and bad contamination of TAM 6.
• 14 Synthesis of TAM 6 Bis{2,2,6,6-tetramethylbenzo[1,2-d:4,5-d′]bis[1,3]dithiol-4-yl}{8-methoxycarbonylmethylthio-2,2,6,6-tetramethylbenzo[1,2-d;4,5-d′]bis[1,3]dithiol-4-yl}methyl (2) A solution of cation 1 was prepared by stirring of solution of triarylmethanol precursor^8a (0.276 g, 0.316 mmol) in anhydrous CH₂Cl₂ (2.5 mL) and CF₃SO₃H (0.060 g, 0.400 mmol, 1.26 equiv) at r.t. for 2.5 h under argon. Slowly, over 20 min, the resulting deep-green solution of cation 1 was added by syringe to a magnetically stirred and cooled (–20 °C) solution of methyl thioglycolate (0.335 g, 3.16 mmol, 20 equiv) in anhydrous toluene (15 mL). The mixture was stirred overnight at room temperature under argon. Water (10 mL) was added, and the mixture was stirred for 5 h at r.t. under air. The organic phase was separated, and the water phase was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic extract was filtered through a short cotton plug and concentrated in vacuo. The resulting solid was dissolved in toluene (20 mL), which was evaporated again to remove residual thioglycolate. Column chromatography on silica gel [hexane, then CH₂Cl₂–hexane (1:1 v/v), then CH₂Cl₂] afforded 3 (0.050 g, 18%), and the title compound 2 (0.194 g, 63%). Spectroscopic data for 2 are the same as in ref. 9. Bis{2,2,6,6-tetramethylbenzo[1,2-d:4,5-d′]bis[1,3]dithiol-4-yl}{8-carboxymethylthio-2,2,6,6-tetramethylbenzo[1,2-d;4,5-d′]bis[1,3]dithiol-4-yl}methyl (6) A mixture of TAM 2 (0.150 g, 0.154 mmol), LiOH monohydrate (0.019 g, 0.463 mmol, 3 equiv), and H₂O (1 mL) in THF (7.5 mL) was stirred at room temperature under argon overnight. The resulting deep-green solution was neutralized by addition of 2 M aq HCl (0.300 mL) and concentrated in vacuo. Subsequent column chromatography on silica gel [CH₂Cl₂, then CH₂Cl₂–MeOH (20:1 v/v), then CH₂Cl₂–MeOH (10:1 v/v)] gave TAM 6 (0.143 g, 97%). Data for 6 Fine black powder mp >280 °C (decomp.). HPLC purity 97%. ESI-MS: m/z calcd for C₃₉H₄₁O₂S₁₃ [M⁺]: 956.9476; found: 956.93; m/z calcd for C₃₉H₄₀O₂S₁₃ [M – H^–]: 955.9403; found: 955.92. IR (KBr): ν = 2955 (s), 2920 (s), 2851 (m), 1707 (s), 1605 (m), 1450 (s), 1431 (m), 1383 (s), 1364 (vs), 1302 (s), 1244 (vs), 1167 (s), 1148 (vs), 1123 (m), 1103 (s), 1030 (m), 683 (m), 660 (m) cm^–1. EPR spectrum for 0.50 mM solution in deoxygenated MeOH: 1:2:1 triplet, α_H=2.263 G, peak-to-peak linewidth 66.5 μT, g = 2.0055. The resolved hyperfine splitting is from the ¹H at the para position on two of the aryl rings. The ¹H hyperfine splitting from the methyl groups of side rings is unresolved with hyperfine splitting constants expected to be similar to those of Finland trityl (less than 0.15 G^4d).
• 15 The tricarboxylic acid 7 is available in large scale (up to 5–10 g) and in high yield with the use of the recently published protocol (Rogozhnikova et al.^8a).
• 16 Tormyshev VM, Genaev AM, Sal’nikov GE, Rogozhnikova OY, Troitskaya TI, Trukhin DV, Mamatyuk VI, Fadeev DS, Halpern HJ. Eur. J. Org. Chem. 2012; 623
• 17 Using MathCad 14.0 and fourth-order Runge–Kutta method with adaptive step size we studied a kinetic model of consecutive hydrolysis of triester. Under the assumption of independent hydrolysis of each of the three initial ester groups, the model predicts the maximum fraction of monocarboxylic acid (44.4%) for reaction of 1 equiv of triester with 1.42 equiv of hydroxide base. Variation of the amount of base in a range between 1.30 and 1.70 equiv results in small changes in the fraction of monocarboxylic acid (43.9–41.5%). For these reasons we chose to use 1.55 equiv of LiOH.
• 18 Synthesis of TAM 12 Tris{8-[methoxycarbonyl]-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d′]bis[1,3]dithiol-4-yl}methanol (8) Prepared according to the method in ref. 16. HPLC purity >95%; mp >230 °C (gradual decomp.). Anal. Calcd for C₄₃H₄₆O₇S₁₂ (1059.60): C, 48.74; H, 4.38; S, 36.31. Found: C, 48.90; H, 4.49; S, 36.04. ESI-HRMS: m/z calcd for C₄₃H₄₆O₇S₁₂ [M⁺]: 1057.9892; found: 1057.9898. IR (KBr): ν = 3313 (m), 2952 (m), 2912 (w), 1712 (s), 1506 (w), 1450 (m), 1433 (m), 1363 (m), 1315 (m), 1251 (s), 1220 (s), 1166 (m), 1105 (m), 1016 (m), 956 (w), 864 (w), 794 (w), 734 (w), 684 (w) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.65 (s, 18 H, CH₃), 1.74 (s, 9 H, CH₃), 1.76 (s, 9 H, CH₃), 3.95 (s, 9 H, CH₃O), 6.78 (s, 1 H, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 28.74 (CH₃C), 29.30 (CH₃C), 31.98 (CH₃C), 33.92 (CH₃C), 52.50 (CH₃O), 61.01 (SCS), 61.12 (SCS), 84.38 (COH), 121.12 (C), 134.14 (C), 139.40 (C), 140.46 (C), 141.58 (C), 142.04 (C), 166.70 (CO₂) ppm Bis{8-(methoxycarbonyl)-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d′]bis[1,3]dithiol-4-yl}{8-carboxyl-2,2,6,6-tetramethylbenzo[1,2-d;4,5-d′]bis[1,3]dithiol-4-yl}methanol (9) A mixture of triester 8 (0.865 g, 0.816 mmol), LiOH monohydrate (0.053 g, 1.26 mmol), and water (1 mL) in THF (5 mL) was stirred at room temperature for 48 h under argon. The resulting mixture was acidified by aq 2 M HCl to pH 4 and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were washed with brine (2 mL) and concentrated in vacuo. Column chromatography on silica gel (CH₂Cl₂–MeOH, 1:20, 1:10, 1:5 v/v) afforded the initial substrate (used further in repeated runs), a mixture of acids 10 and 11 (used for conversion to initial substrate by method of ref. 14) and the title monocarboxylic acid 9. Three iterations afforded 0.553 g of 9 (65%) with partial recovery of precursor 8 (0.115 g, 14%). Yellow powder; HPLC purity >95%; mp >200 °C (gradual decomp.). Anal. Calcd for C₄₂H₄₄O₇S₁₂ (1045.57): C, 48.25; H, 4.24; S, 36.80. Found: C, 48.57; H, 4.40; S, 36.45. ESI-HRMS: m/z calcd for C₄₂H₄₃O₇S₁₂ [M – H^–]: 1042.9663; found: 1042.9630. IR (KBr): ν = 3429 (m), 2954 (m), 2922 (m), 2854 (m), 1712 (s), 1585 (m), 1506 (m), 1452 (m), 1435 (m), 1382 (m), 1365 (s), 1336 (m), 1315 (m), 1249 (s), 1224 (s), 1166 (m), 1149 (m), 1103 (m), 1016 (m), 912 (w), 864 (w), 792 (w), 732 (w), 704 (w) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.55–1.72 (singlet signals of methyl groups, 36 H, CH₃), 3.87 (s, 6 H, CH₃O), 6.79 (s, 1 H, OH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ =27.16 (CH₃C), 27.70 (CH₃C), 27.73 (CH₃C), 27.83 (CH₃C), 28.50 (CH₃C), 29.46 (CH₃C), 30.60 (CH₃C), 31.22 (CH₃C), 32.23 (CH₃C), 33.54 (CH₃C), 33.86 (CH₃C), 52.23 (CH₃O), 59.32 (SCS), 59.90 (SCS), 60.40 (SCS), 60.64 (SCS), 60.83 (SCS), 60.89 (SCS), 83.47 (COH), 120.46 (C), 120.60 (C), 130.59 (C), 133.90 (C), 134.15 (C), 136.19 (C), 138.44 (C), 138.70 (C), 139.06 (C), 139.68 (C), 139.71 (C), 139.76 (C), 139.97 (C), 140.30 (C), 140.38 (C), 140.45(C), 140.59 (C), 165.53 (CO₂CH₃), 168.63 (CO₂H) ppm. Bis{8-(methoxycarbonyl)-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d′]bis[1,3]dithiol-4-yl}{8-carboxyl-2,2,6,6-tetramethylbenzo[1,2-d;4,5-d′]bis[1,3]dithiol-4-yl}methyl (12)To solution of 9 (0.115 g, 0.110 mmol) in anhydrous CH₂Cl₂ (1 mL) was added a solution of TfOH (0.082 g, 0.550 mmol) in anhydrous MeCN (0.5 mL). The resulting deep-green solution was stirred under argon for 5 min at room temperature, after which a solution of SnCl₂ (0.022 g, 0.116 mmol) in anhydrous THF (1 mL) was added. After stirring under argon for 8 min at room temperature the mixture was quenched by addition of water (20 mL) followed by addition of CH₂Cl₂ (10 mL). The organic phase was separated, and the water phase was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic extract was filtered through a short cotton plug and concentrated in vacuo. Column chromatography on silica gel [CH₂Cl₂, then CH₂Cl₂–MeOH (20:1 v/v)] afforded TAM 12 (0.107 g, 95%). Fine black powder; mp >280 °C (decomp.). HPLC purity 98.6%. ESI-MS: m/z calcd for C₄₂H₄₃O₆S₁₂ [M⁺]: 1026.9708; found: 1026.973; m/z calcd for C₄₂H₄₂O₆S₁₂ [M – H^–]: 1025.9635; found: 1025.959. IR (KBr): ν = 2953 (m), 2922 (m), 1706 (s), 1452 (m), 1433 (m), 1366 (m), 1273 (m), 1234 (vs), 1167 (m), 1148 (m), 1136 (m), 1111 (m), 864 (w), 721 (w) cm^–1. EPR spectrum for 0.50 mM solution in anaerobic MeOH: sept α_H = 0.0992 G (6 H), peak-to-peak linewidth 7.7 μT (Lorentzian) and 2.1 μT (Gaussian), g = 2.0056. The observed hyperfine splitting is caused by six-proton nuclei of COOCH₃ present at the para position on two of the aryl rings.
• 19 The analogous series of iterations performed with trimethyl ester of the paramagnetic triacid (Finland trityl) was accompanied by formation by numerous high-molecular contaminants and resulted in lower isolated yield (51%) of TAM 12 after three repetitive runs.
• 20 Synthesis of Biradical 13 A solution of dicyclohexylcarbodiimide (0.014 g, 0.067 mmol) in CH₂Cl₂ (0.5 mL) was added slowly with cooling on an ice-bath to a stirred solution of N-hydroxysuccinimide (0.081 g, 0.070 mmol) and TAM 6 (0.056 g, 0.058 mmol) in anhydrous CH₂Cl₂ (1 mL). The mixture was stirred under argon at room temperature for 4 h and then concentrated in vacuo. The resulting cake was dissolved in toluene (5 mL), the solution was filtered through a short cotton plug. Concentration of the filtrate in vacuo afforded the OSU derivative of TAM 6. It was dissolved in 0.023 M solution of N,N′-dimethylethylenediamine in CH₂Cl₂ (1 mL, 0.023 mmol of diamine). The mixture was stirred under argon at room temperature for 36 h and quenched by addition of 0.01 M of aq HCl. The organic phase was separated, and the water phase was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic extract was filtered through a short cotton plug and concentrated in vacuo. Column chromatography on silica gel [CH₂Cl₂, then CH₂Cl₂–EtOAc (20:1 v/v), then CH₂Cl₂–EtOAc (10:1 v/v)] afforded the biradical 13 (0.042 g, 94% of initial diamine). Data for 13 Fine dark brown powder; mp >280 °C. HPLC purity 94.6%. ESI-MS: m/z calcd for C₈₂H₉₀N₂O₂S₂₆ [M⁺]: 1965.9741; found: 1965.975. IR (KBr): ν = 2955 (s), 2922 (s), 2853(m), 1734 (m), 1651 (vs), 1452 (s), 1433 (m), 1396 (m), 1383 (m), 1364 (s), 1302 (m), 1244 (vs), 1167 (s), 1150 (vs), 1103 (m), 847 (w), 685 (w) cm^–1. The EPR spectrum for a 0.50 mM solution of biradical 13 in degassed CH₂Cl₂ has five equally spaced lines caused by the hyperfine coupling to the four proton nuclei that are the X groups. The peak-to-peak line intensities appear to be in the ratio of 1:1:2:1:1 rather than the 1:4:6:4:1 expected for four equivalent proton nuclei. However, the outer and center lines are noticeably sharper than the other two lines, a classic example of the alternating linewidth effect resulting from the limited tumbling rate (compared to the hyperfine anisotropy) of such a large molecule (>2 nm long) in solution. The hyperfine coupling (α_H = ca. 1 G) is about half that of 6, showing that the electron spin–spin interaction between the TAM is much larger than the α_H = ca. 2 G of 6 (see Supporting Information).
• 21 Synthesis of Biradical 14 To a stirred solution of TAM 12 (0.034 g, 0.033 mmol) and Et₃N (0.012 g, 0.116 mmol) in anhydrous CHCl₃ (1 mL) slowly was added a solution of SOCl₂ (0.027 g, 0.231 mmol) in CHCl₃ (0.2 mL). The mixture was stirred under argon at room temperature for 20 h and then concentrated in vacuo. The resulting cake was dissolved in toluene (5 mL), the solution was filtered through a short cotton plug. Concentration of the filtrate in vacuo afforded the chloroanhydride of 12. It was dissolved in 0.023 M solution of N,N′-dimethylethylenediamine in CH₂Cl₂ (0.57 mL, 0.0132 mmol of diamine). Et₃N (0.010 g, 0.10 mmol) and 4-dimethylaminopyridine (0.004 g) were added. The mixture was stirred under argon at room temperature for 36 h and quenched by addition of 0.01 M of aq HCl. The organic phase was separated, and the water phase was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic extract was filtered through a short cotton plug and concentrated in vacuo. Column chromatography on silica gel [CH₂Cl₂, then CH₂Cl₂–EtOAc (30:1 v/v)] gave the biradical 14 (0.020 g, 72% of initial diamine). Data for 14 Fine black powder; mp >280 °C. HPLC purity 96.6%. ESI-MS: m/z calcd for C₈₉H₉₄N₂O₁₀S₂₄ [M⁺]: 2106.0205; found: 2106.021. IR (KBr): ν = 2953 (m), 2920 (m), 2860 (w), 1707 (s), 1641 (s), 1485 (m), 1452 (m), 1433 (m), 1366 (m), 1265 (s), 1236 (vs), 1167 (m), 1136 (m), 1109 (m), 1043 (m), 864 (w), 789 (w), 729 (w) cm^–1. The EPR spectrum for a 0.50 mM solution of biradical 14 in degassed CH₂Cl₂ consists of a single sharp line flanked by a pair of weak lines from natural abundance ¹³C hyperfine (see Supporting Information). The hyperfine couplings from the methyl ester H are expected to produce at least 13 lines split by <0.1 G (based on the α_H of 12). Each of those lines is further split into five lines by weak hyperfine interactions with the two N. The result is expected to be the single, unresolved line that is observed.