Hexacarboxylic Acid Biscavitands

Abstract

The synthesis of hexacarboxylic acid biscavitands is described. These new singly bridged biscavitands are based on resorcin[4]arene with a flexible all-carbon bridge at one 2-resorcyl position and carboxylic acids at the remaining 2-resorcyl positions. Preliminary self-assembling behavior of these new biscavitands is described.

cavitand - biscavitand - self-assembly - lithiation

References

1a Cram DJ. Cram JM. Container Molecules and Their Guests   Royal Society of Chemistry; Cambridge: 1994. 

1b Jasat A. Sherman JC. Chem. Rev.  1999,  99:  931 

1c Warmuth R. Yoon J. Acc. Chem. Res.  2001,  34 (2):  95 

1d Rudkevich DM. Bull. Chem. Soc. Jpn.  2002,  75:  393 

2a Rebek J. Acc. Chem. Res.  1999,  32:  278 

2b Hof F. Craig SL. Nuckolls C. Rebek J. Angew. Chem. Int. Ed.  2002,  41:  1488 

2c Atwood JL. Barbour LJ. Jerga A. Proc. Natl. Acad. Sci. U.S.A.  2002,  99 (8):  4837 

2d Shivanyuk A. Rebek J. J. Am. Chem. Soc.  2003,  125:  3432 

2e Kobayashi K. Ishii K. Sakamoto S. Shirasaka T. Yamaguchi K. J. Am. Chem. Soc.  2003,  125:  10615 

3a Flauaus M. Herzing M. Köllhofer A. Laly M. Plenio H. Eur. J. Org. Chem.  2001,  1061 

3b Sliwa W. Deska M. Chem. Heterocycl. Compd.  2002,  38 (6):  646 

4a Chapman RG. Olovsson G. Trotter J. Sherman JC. J. Am. Chem. Soc.  1998,  120:  6252 

4b Heinz T. Rudkevich DM. Rebek J. Nature  1998,  394:  764 

4c Kobayashi K. Shirasaka T. Yamaguchi K. Sakamoto S. Horn E. Furukawa N. Chem. Commun.  2000,  41 

4d Körner SK. Tucci FC. Rudkevich DM. Heinz T. Rebek J. Chem.-Eur. J.  2000,  6 (1):  187 

Some examples of biscavitands:

5a Chapman RG. Sherman JC. J. Am. Chem. Soc.  1998,  120:  9818 

5b Irwin JL. Sherburn MS. Org. Lett.  2001,  3:  225 

5c Barrett ES. Irwin JL. Turner P. Sherburn MS. Org. Lett.  2002,  4 (9):  1455 

5d Paek K. Gutierrez Tunstad LM. Maverick EF. Knobler CB. Cram DJ. J. Inclusion Phenom. Macrocyclic Chem.  2003,  45:  203 

6 Peczuh MW. Hamilton AD. Chem. Rev.  2000,  100:  2479 

7

General Procedure for Making Biscavitands 2a-c: To a stirred solution of cavitand 1 (0.5 mmol) in freshly dried THF (20 mL) at -78 °C under Ar, n-BuLi in hexanes (1.6 M, 1.10 equiv) was added via syringe. After 15 min at -78 °C, the dry ice-acetone bath was removed. Stirring was continued for 15 min, then at -78 °C, the diiodoalkane (0.48 equiv) was added. The reaction mixture was slowly warmed to ambient temperature with stirring over 2 h. The solvent was then removed in vacuo. Brine (20 mL) and 10% HCl (10 mL) were added to the residue, which was then extracted with Et₂O (50 mL). The ether extract was dried over MgSO₄, evaporated in vacuo, and the crude was separated by flash chromatography on silica gel, yielding the desired biscavitands.

8

Biscavitand 2a: 35% yield; mp 166 °C (dec.). ¹H NMR (300 MHz, CDCl₃): δ = 7.09 (s, 6 H, bottom Ar-H), 6.95 (s, 2 H, bottom Ar-H), 6.46 (s, 6 H, top Ar-H), 5,74 (d, J = 4.8 Hz, 4 H, outer of -CHH-), 5.72 (d, J = 5.1 Hz, 4 H, outer of -CHH-), 4.69 (m, 8 H, Ar₂ CH-, two overlapping triplets), 4.39 (d, J = 7.2 Hz, 4 H, inner of -CHH-), 4.30 (d, J = 7.2 Hz, 4 H, inner of -CHH-), 2.27 (m, 4 H, -CH ₂CH₂CH₂-
CH ₂-), 2.19 [m, 16 H, -CH ₂ (CH₂)₃CH₃], 1.34 [m, 52 H,
-CH₂(CH ₂ ) ₃ CH₃ and -CH₂ CH ₂ CH ₂ CH₂-], 0.89 [t, J = 6.0 Hz, 24 H, -CH₂ (CH₂)₃ CH ₃ ]. ¹³C NMR (75 MHz, CDCl₃): δ = 155.1, 154.9, 153.4, 138.6, 138.4, 138.1, 128.4, 120.9, 120.8, 117.8, 116.6, 116.4, 99.7, 99.5, 36.9, 36.5, 32.2, 30.2, 30.0, 27.8, 27.7, 25.6, 22.9, 14.3. HRMS-MALDI: m/z calcd for C₁₀₈H₁₃₄O₁₆Na [M + Na]⁺: 1709.9564 (error 1.9 ppm). Found: 1709.9596.

9

Biscavitand 2b: 32% yield; mp 157 °C (dec.). ¹H NMR (300 MHz, CDCl₃): δ = 7.09 (s, 6 H, bottom Ar-H), 6.95 (s, 2 H, bottom Ar-H), 6.45 (s, 6 H, top Ar-H), 5.78 (d, J = 7.2 Hz, 4 H, outer of -CHH-), 5.72 (d, J = 7.2 Hz, 4 H, outer of
-CHH-), 4.70 (t, J = 7.8 Hz, 8 H, Ar₂ CH-), 4.39 (d, J = 7.2 Hz, 4 H, inner of -CHH-), 4.32 (d, J = 7.2 Hz, 4 H, inner of -CHH-), 2.27 [m, 4 H, -CH ₂ (CH₂)₃ CH ₂ -], 2.21 [m, 16 H, -CH ₂ (CH₂)₃CH₃], 1.36 [m, 54 H, -CH₂ (CH ₂ ) ₃ CH₃ and
-CH₂ (CH ₂ ) ₃ CH₂-], 0.88 [t, J = 6.0 Hz, 24 H,
-CH₂(CH₂)₃ CH ₃ ]. ¹³C NMR (75 MHz, CDCl₃): δ = 155.1, 154.9, 153.4, 138.6, 138.4, 138.1, 128.6, 120.9, 120.8, 117.8, 116.6, 116.5, 99.7, 99.5, 36.9, 36.5, 32.2, 30.2, 30.0, 29.8, 27.7, 25.6, 22.9, 14.3; HRMS-MALDI: m/z calcd for C₁₀₉H₁₃₆O₁₆Na [M + Na]⁺: 1723.9726 (error -0.4 ppm). Found: 1723.9713.

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Biscavitand 2c: 30% yield; mp 150 °C (dec.). ¹H NMR (300 MHz, CDCl₃): δ = 7.11 (s, 6 H, bottom Ar-H), 6.96 (s, 2 H, bottom Ar-H), 6.47 (s, 6 H, top Ar-H), 5.79 (d, J = 7.2 Hz, 4 H, outer of -CHH-), 5.73 (d, J = 7.2 Hz, 4 H, outer of
-CHH-), 4.72 (t, J = 7.8 Hz, 8 H, Ar₂ CH-), 4.41 (d, J = 7.2 Hz, 4 H, inner of -CHH-), 4.34 (d, J = 7.2 Hz, 4 H, inner of -CHH-), 2.26 [m, 4 H, -CH ₂ (CH₂)₄CH ₂ -], 2.23 [m, 16 H, -CH ₂ (CH₂)₃CH₃], 1.35 [m, 56 H, -CH₂ (CH ₂ ) ₃ CH₃ and
-CH₂ (CH ₂ ) ₄ CH₂-], 0.89 [t, J = 6.0 Hz, 24 H,
-CH₂(CH₂)₃ CH ₃ ]. ¹³C NMR (75 MHz, CDCl₃): δ = 155.1, 154.9, 153.3, 138.6, 138.4, 138.1, 128.7, 120.9, 120.8, 117.7, 116.5, 116.4, 99.7, 99.5, 36.9, 36.5, 32.2, 30.1, 30.0, 29.7, 27.7, 25.6, 22.9, 14.2. HRMS-MALDI: m/z calcd for C₁₁₀H₁₃₈O₁₆Na [M + Na]⁺: 1737.9877 (error 0.69 ppm). Found: 1737.9889.

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General Procedure for Making Hexacarboxylic Acid Biscavitands 3a-c: To a stirred solution of biscavitand 2 (0.2 mmol) in freshly dried THF (15 mL) at -78 °C under Ar, n-BuLi (1.6 M in hexanes, 6.6 equiv) was added in one portion via syringe. The resulting mixture was stirred at
-78 °C for 10 min, the cooling bath was removed and stirring was continued for an additional 10 min. The ice bath was replaced and ‘bone dry’ grade CO₂ (Gilmore Liquid Air Company, South El Monte, CA 91733) was bubbled into the reaction mixture for 15 min (white solids formed immediately). The reaction was quenched with 1.0 N HCl (2.0 mL). THF was evaporated in vacuo. The white solids were collected by filtration and washed thoroughly with H₂O, then dried in vacuo. This material was used in the self-assembly studies. Further purification by recrystallization from CH₂Cl₂-acetone was carried out. The recovery yields, however, were less than 40%. No signal for lower homologs was detected after recrystallization.

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Biscavitand 3a: 97% yield; mp 215 °C (dec.). ¹H NMR (300 MHz, acetone-d ₆): δ = 7.73 (s, 2 H, bottom Ar-H), 7.68 (s, 4 H, bottom Ar-H), 7.47 (s, 2 H, bottom Ar-H), 5.82 (d, J = 7.5 Hz, 4 H, outer of -CHH-), 5.74 (d, J = 7.5 Hz, 4 H, outer of -CHH-), 4.76 (t, J = 7.2 Hz, 8 H, Ar₂ CH-), 4.50 (d, J = 7.5 Hz, 4 H, inner of -CHH-), 4.42 (d, J = 7.5 Hz, 4 H, inner of -CHH-), 2.41 [m, 20 H, -CH ₂CH₂CH₂CH ₂- and
-CH ₂ (CH₂)₃CH₃], 1.33 [52 H, m, -CH₂ (CH ₂ ) ₃ CH₃ and
-CH₂ CH ₂ CH ₂ CH₂-], 0.89 [m, 24 H, -CH₂(CH₂)₃ CH ₃ ]. ¹³C NMR (75 MHz, acetone-d ₆): δ = 166.3, 154.3, 152.1, 151.6, 151.3, 140.0, 139.7, 138.9, 138.5, 130.7, 125.6, 125.5, 123.6, 123.4, 119.5, 100.6, 100.1, 39.8, 37.9, 37.5, 32.7, 32.6, 30.8, 30.5, 28.5, 26.4, 23.9, 23.4, 14.4. HRMS-MALDI: m/z calcd for C₁₁₄H₁₃₄O₂₈Na [M + Na]⁺: 1973.8954 (error -5.5 ppm). Found: 1973.8845.

13

Biscavitand 3b: 95% yield; mp 206 °C (dec.). ¹H NMR (300 MHz, acetone-d ₆): δ = 7.72 (s, 2 H, bottom Ar-H), 7.67 (s, 4 H, bottom Ar-H), 7.46 (s, 2 H, bottom Ar-H), 5.79 (d, J = 7.5 Hz, 4 H, outer of -CHH-), 5.72 (d, J = 7.5 Hz, 4 H, outer of -CHH-), 4.76 (t, J = 7.2 Hz, 8 H, Ar₂ CH-), 4.50 (d, J = 7.5 Hz, 4 H, inner of -CHH-), 4.43 (d, J = 7.5 Hz, 4 H, inner of -CHH-), 2.40 [m, 20 H, -CH ₂ (CH₂)₃ CH ₂ - and
-CH ₂ (CH₂)₃CH₃], 1.38 [m, 54 H, -CH₂ (CH ₂ ) ₃ CH₃ and
-CH₂ (CH ₂ ) ₃ CH₂-], 0.91 [m, 24 H, -CH₂(CH₂)₃ CH ₃ ]. ¹³C NMR (75 MHz, acetone-d ₆): δ = 166.4, 154.3, 152.0, 151.7, 151.4, 140.0, 139.7, 138.9, 138.5, 130.6, 125.8, 125.7, 123.5, 123.4, 119.5, 100.6, 100.2, 40.5, 39.8, 37.9, 37.5, 32.7, 32.6, 30.5, 28.4, 26.4, 24.1, 23.4, 14.4. HRMS-MALDI: m/z calcd for C₁₁₅H₁₃₇O₂ [M + H]⁺: 1965.9291 (error -2.9 ppm). Found: 1965.9234.

14

Biscavitand 3c: 97% yield; mp 198 °C (dec.). ¹H NMR (300 MHz, acetone-d ₆): δ = 7.72 (s, 2 H, bottom Ar-H), 7.68 (s, 4 H, bottom Ar-H), 7.46 (s, 2 H, bottom Ar-H), 5.78 (d, J = 7.5 Hz, 4 H, outer of -CHH-), 5.72 (d, J = 7.5 Hz, 4 H, outer of -CHH-), 4.76 (t, J = 7.2 Hz, 8 H, Ar₂ CH-), 4.50 (d, J = 7.5 Hz, 4 H, inner of -CHH-), 4.42 (d, J = 7.5 Hz, 4 H, inner of -CHH-), 2.38 [m, 20 H, -CH ₂ (CH₂)₄ CH ₂ - and
-CH ₂ (CH₂)₃CH₃], 1.37 [m, 56 H, -CH₂ (CH ₂ ) ₃ CH₃ and
-CH₂ (CH ₂ ) ₄ CH₂-], 0.91 [m, 24 H, -CH₂(CH₂)₃ CH ₃ ]. ¹³C NMR (75 MHz, acetone-d ₆): δ = 166.3, 154.2, 152.1, 151.6, 151.4, 140.0, 139.7, 138.9, 138.5, 130.7, 125.7, 125.5, 123.6, 123.5, 119.5, 100.6, 100.1, 39.8, 37.8, 37.5, 32.7, 32.6, 30.4, 28.4, 26.4, 24.1, 23.3, 14.3. HRMS-MALDI: m/z calcd for C₁₁₆H₁₃₈O₂₈Na [M + Na]⁺: 2001.9272 (error
-1.2 ppm). Found: 2001.9242.

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