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Synthesis and conformation of unsubstituted calix[4]arene
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Tetrahedron Letters, Vo1.32,No.41. Pp 5655-5658.1991 Printed in Great Britain
Synthesis and Conformation
of Unsubstituted
John E. McMurry* and J. Christopher Department
of Chemistry,
Baker Laboratory,
Phelan
Cornell University,
Key Words: calixarene; conformation;
cyclophane;
Calix[4]arene
Ithaca, NY
14853-1301
macrocycle.
Abstract: The title compound was prepared and its structure was investigated by single-crystal X-ray diffractometry. The conformation of the molecule in the crystalline state was found to be different from those conformations formerly reported for substituted calix[4]arenes. Molecular mechanics calculations indicate tkzt theconformation in the crystal does not represent an energy minimum.
Substituted calix[4]arenes have received a large amount of attention in recent years owing to their ability Somewhat surprisingly, however, the unsubstituted parent to complex cations and small molecules.’ compound (4)2 has not been reported. In the hope that 4 might show unusual properties as a hydrocarbon ligand for preparing new kinds of organometallic sandwich compounds, we have now synthesized and characterized this substance by the route shown in the Scheme.
2
1
Scheme. Synthesis of calix[4]arene -78°C; (c) AICls, toluene,
3
(a) HPO(OEt)z,
CC4,50%
aq. NaOH, Bu4NBr; (b) K, NH3, THF,
-5’C.
The phenolic hydroxyl groups of tetrahydroxytetra-rert-butylcalix[4]arene (1) were removed by a modification of the method reported by Goren and Biali.3 Diethyl phosphite (1.7 eq/OH) was added to a mixture of l4 (19.97 g, 30.8 mmol), B@VBr (0.10 eq/OH), 50% aq. NaOH (65 mL), and CC4 (350 mL), and the reaction mixture was stirred for 1 h at room temperature. The product was washed with brine, dried (MgSOd), and concentrated at the rotary evaporator to give 32.77 g of crude phosphate ester 2, which was dissolved in dry ether (200 mL) and added to a solution of potassium (-20 g, large excess) in liquid ammonia (600 mL) at -78°C. After warming to reflux, retooling, and quenching by addition of soiid NH&l, extraction of the reaction residue with 3: 1 hexane/toluene, filtration through silica gel, and removal of solvent at the rotary evaporator gave 3 as a light yellow solid in a yield of 68%. The tert-butyl groups were then removed by transalkylation with toluene.5 Compound 3 (0.128 g, 0.22 mmol) was dissolved in dry toluene (10 mL) at -5’C, solid AlCls (2.4 g, 2.0 eqlt-Bu) was added, and the mixture was stirred 1 h before quenching with 2 M HCl. Removal of solvent at the rotary evaporator, removal of tert-butyltoluene by Kugelrohr distillation, and recrystallization of the residue from isopropanol/acetone gave 4 as colorless needles, mp 198-199”C, in 47% yield (37.5 mg). The product was characterized by ‘H and 13C NMR, IR, and mass spectroscopy.6 5655
56.56
A single crystal of 4 grown from 2-butanone was selected for X-ray crystallography and cut to 0.2 x 0.3 x 0.6 mm. Data were collected (2002 reflections) using MO Ka radiation on a Syntex P2t four-circle diffractometer, and processed using the SHELXTL software package on a MicroVAX II computer running VMS. A satisfactory solution for the structure was obtained by direct methods in the P2i/n space group. The unit-cell dimensions in angstroms and degrees were a = 7.9168, b = 7.4817, c = 17.4163, a = 90.027, p = 100.144, y = 89.894, and the final R values were R = 0.0728 and wR = 0.0825. The structure is shown in Figures 1 and 2.
Figure
1.Two views of calix[4]arene
Figure 2. Packing of calix[4]arene
(4) in the chair conformation.
molecules
in the crystal.
Substituted calix[4]arenes commonly show four conformations, termed by Gutsche the cone, partial As shown in Figure 1, however, calix[4]arene 4 has cone, 1,2-alternate, and 1,3-alternate arrangements.’ none of the four but instead has an unusual chair-like conformation with two aromatic rings lying in a plane and the other two other aromatic rings at right angles.8 When they pack together in the crystal, the individual molecules stack up like slightly offset chairs. In an attempt to understand the confotmational behavior of 4, molecular mechanics calculations’ were carried out and a full conformational search was done using the 1,3-alternate conformation as a starting point. Over 100 different conformations were found within a 3 kcal/mol energy range, including the expected cone 4a (lowest in energy), the 1,3-alternate 4c (tenth lowest in energy), and numerous others. Interestingly, the conformation determined by X-ray analysis does not lie at an energy minimum. Using the X-ray coordinates for the input geometry, the crystal stmcture minimizes to a different and more stable chair conformation that itself has an MMX energy of 42.63 kcal/mol, nearly 3 kcal/mol higher than the cone. Clearly, the energy that results from favorable packing of molecules in the crystal is more than able to compensate for the higher steric energy of the chair conformation.
5657
4a (Cone; 39.97 kcal/mol)
4c (1,3-Alternate;
40.79 kcal/mol)
4 (Chair, minimized - 42.63 kcal/mol)
Figure 3. Conformations
of calix[4]arene.
4b (Partial cone; 40.64 kcal/mol)
4d (1,2-Alternate;
41.48 kcal/mol)
4 (Chair; X ray)
The X-ray structure does not lie at an energy minimum.
The ‘H Nh4R spectrum of 1 in CD2C12 at 300 MHz shows a singlet at 3.87 6 for the benzylic methylene protons, and no appreciable broadening of the signal is observed when the sample is cooled from room temperature to 188 K. Although this kind of negative evidence must be viewed with caution, it confirms the results of the molecular mechanics calculations by suggesting a molecule of considerable conformational flexibility.”
5658
roperties substantially Our results show that the parent calix[4]arene (4) has conformational different from those of previously studied calix[4]arenes as reported by Gutsche. ? In the crystalline state, the removal of the oxygen substituents allows two opposing phenyl rings to become nearly coplanar, with the other two rings perpendicular to the plane. In solution, the same reduced steric bulk renders the molecule conformationally flexible, and there is little barrier to rotation about the aryl-methylene bonds. Acknowledgements: the National Institutes
We thank Jorge L. Rios for assistance in the X-ray diffractometry experiment and of Health for financial support to J. C. Phelan through Training Grant GM07273. References
1. 2. 3. 4. 5. 6.
7. 8.
9.
10.
and Notes
For a comprehensive review of all aspects of calixarene chemistry, see: Gutsche, C. D. Culixarenes, Royal Society of Chemis Cambridge, 1989. n? 3.1’5~‘9]octacosa-l(25),3,5,7(28),9,11,13(27),15,17,19(26),21,233*7.19* Pentacyclo[l9.3.1.1 dodecaene is the IUPAC name of 4. Goren, A.; Biali, S.E. J. Chem. Sot. Perkin Trans. I 1990, 1484-1487. Diethylchlorophosphate was prepared in situ by reaction of diethylphosphite with CC4: Zwierzak, A. Synthesis 1976, 305-306. Gutsche, C.D.; Iqbal, M.; Stewart, D. J. Org. Chem. 1986,51,742-745. Gutsche, C.D.; Levine, J.A.; Sujeeth, P.K. J. Org. Chem. 1985,50, 5802-5806. tH NMR (300 MHz, CDCls) 6 7.23 (t, J=8.0 Hz, ArH), 7.10 (d, J=8.0 Hz, ArH), 6.72 (s, ArH), 3.87 (s, CH2). 13C NMR (75 MHz, CDCls) 6 141.5 (4’Ar), 129.0, 128.4, 126.8 (3’Ar), 42.0 (CH 2). FTIR (CC4, in cm-‘) 3060 w, 3030 w, 2920 w, 2850 w, 2300 w, 1600 s (Ar), 1440, 1250 s, 1220 s, 1110, 1090, 1070, 1000 s, 980 s. MS (EI) m/e (rel intensity) 360 (25, Mf), 180 (33), 179 (91), 178 (78), 166 (36) 165 (lOtI), 105 (29), 104 (71), 91 (64). HRMS (EI) m/e 360.1874; Calc’d. for C2sH24, 360.1878. Gutsche, C.D. Act. Chem. Res. 1983,16, 161-170. This chair conformation has been previously observed with resorcinol-derived calixarenes having substituents on the bridging methylene groups: Hogberg, A. J. S. J. Am. Chem. Sot, 1980,102,60466050. Minimizations were done with PCMODEL version 4.0 (Serena Software, Bloomington, Indiana 47402-3076), on a Silicon Graphics Personal Iris workstation. The conformational search was done using MODEL Version KS 2.7 (K. Steliou, University of Montreal, and W.C. Still, Columbia University) with the MM2 force field and batch-mode MMX (Y.H. Yuh & N.L. Allinger; adaptation, modifications, and constants by J.J. Gajewski, K.E. Gilbert, J. McKelvey, and W.C. Still) on a DEC VAX 8530 running VMS. In principle, the lack of NMR coalescence might also be caused by the molecule adopting exclusively the 1,3-alternate conformation in solution, a conformation in which the methylene protons are equivalent. (Received in USA 16 July 1991)
Tetrahedron Letters, Vo1.32,No.41. Pp 5655-5658.1991 Printed in Great Britain
Synthesis and Conformation
of Unsubstituted
John E. McMurry* and J. Christopher Department
of Chemistry,
Baker Laboratory,
Phelan
Cornell University,
Key Words: calixarene; conformation;
cyclophane;
Calix[4]arene
Ithaca, NY
14853-1301
macrocycle.
Abstract: The title compound was prepared and its structure was investigated by single-crystal X-ray diffractometry. The conformation of the molecule in the crystalline state was found to be different from those conformations formerly reported for substituted calix[4]arenes. Molecular mechanics calculations indicate tkzt theconformation in the crystal does not represent an energy minimum.
Substituted calix[4]arenes have received a large amount of attention in recent years owing to their ability Somewhat surprisingly, however, the unsubstituted parent to complex cations and small molecules.’ compound (4)2 has not been reported. In the hope that 4 might show unusual properties as a hydrocarbon ligand for preparing new kinds of organometallic sandwich compounds, we have now synthesized and characterized this substance by the route shown in the Scheme.
2
1
Scheme. Synthesis of calix[4]arene -78°C; (c) AICls, toluene,
3
(a) HPO(OEt)z,
CC4,50%
aq. NaOH, Bu4NBr; (b) K, NH3, THF,
-5’C.
The phenolic hydroxyl groups of tetrahydroxytetra-rert-butylcalix[4]arene (1) were removed by a modification of the method reported by Goren and Biali.3 Diethyl phosphite (1.7 eq/OH) was added to a mixture of l4 (19.97 g, 30.8 mmol), B@VBr (0.10 eq/OH), 50% aq. NaOH (65 mL), and CC4 (350 mL), and the reaction mixture was stirred for 1 h at room temperature. The product was washed with brine, dried (MgSOd), and concentrated at the rotary evaporator to give 32.77 g of crude phosphate ester 2, which was dissolved in dry ether (200 mL) and added to a solution of potassium (-20 g, large excess) in liquid ammonia (600 mL) at -78°C. After warming to reflux, retooling, and quenching by addition of soiid NH&l, extraction of the reaction residue with 3: 1 hexane/toluene, filtration through silica gel, and removal of solvent at the rotary evaporator gave 3 as a light yellow solid in a yield of 68%. The tert-butyl groups were then removed by transalkylation with toluene.5 Compound 3 (0.128 g, 0.22 mmol) was dissolved in dry toluene (10 mL) at -5’C, solid AlCls (2.4 g, 2.0 eqlt-Bu) was added, and the mixture was stirred 1 h before quenching with 2 M HCl. Removal of solvent at the rotary evaporator, removal of tert-butyltoluene by Kugelrohr distillation, and recrystallization of the residue from isopropanol/acetone gave 4 as colorless needles, mp 198-199”C, in 47% yield (37.5 mg). The product was characterized by ‘H and 13C NMR, IR, and mass spectroscopy.6 5655
56.56
A single crystal of 4 grown from 2-butanone was selected for X-ray crystallography and cut to 0.2 x 0.3 x 0.6 mm. Data were collected (2002 reflections) using MO Ka radiation on a Syntex P2t four-circle diffractometer, and processed using the SHELXTL software package on a MicroVAX II computer running VMS. A satisfactory solution for the structure was obtained by direct methods in the P2i/n space group. The unit-cell dimensions in angstroms and degrees were a = 7.9168, b = 7.4817, c = 17.4163, a = 90.027, p = 100.144, y = 89.894, and the final R values were R = 0.0728 and wR = 0.0825. The structure is shown in Figures 1 and 2.
Figure
1.Two views of calix[4]arene
Figure 2. Packing of calix[4]arene
(4) in the chair conformation.
molecules
in the crystal.
Substituted calix[4]arenes commonly show four conformations, termed by Gutsche the cone, partial As shown in Figure 1, however, calix[4]arene 4 has cone, 1,2-alternate, and 1,3-alternate arrangements.’ none of the four but instead has an unusual chair-like conformation with two aromatic rings lying in a plane and the other two other aromatic rings at right angles.8 When they pack together in the crystal, the individual molecules stack up like slightly offset chairs. In an attempt to understand the confotmational behavior of 4, molecular mechanics calculations’ were carried out and a full conformational search was done using the 1,3-alternate conformation as a starting point. Over 100 different conformations were found within a 3 kcal/mol energy range, including the expected cone 4a (lowest in energy), the 1,3-alternate 4c (tenth lowest in energy), and numerous others. Interestingly, the conformation determined by X-ray analysis does not lie at an energy minimum. Using the X-ray coordinates for the input geometry, the crystal stmcture minimizes to a different and more stable chair conformation that itself has an MMX energy of 42.63 kcal/mol, nearly 3 kcal/mol higher than the cone. Clearly, the energy that results from favorable packing of molecules in the crystal is more than able to compensate for the higher steric energy of the chair conformation.
5657
4a (Cone; 39.97 kcal/mol)
4c (1,3-Alternate;
40.79 kcal/mol)
4 (Chair, minimized - 42.63 kcal/mol)
Figure 3. Conformations
of calix[4]arene.
4b (Partial cone; 40.64 kcal/mol)
4d (1,2-Alternate;
41.48 kcal/mol)
4 (Chair; X ray)
The X-ray structure does not lie at an energy minimum.
The ‘H Nh4R spectrum of 1 in CD2C12 at 300 MHz shows a singlet at 3.87 6 for the benzylic methylene protons, and no appreciable broadening of the signal is observed when the sample is cooled from room temperature to 188 K. Although this kind of negative evidence must be viewed with caution, it confirms the results of the molecular mechanics calculations by suggesting a molecule of considerable conformational flexibility.”
5658
roperties substantially Our results show that the parent calix[4]arene (4) has conformational different from those of previously studied calix[4]arenes as reported by Gutsche. ? In the crystalline state, the removal of the oxygen substituents allows two opposing phenyl rings to become nearly coplanar, with the other two rings perpendicular to the plane. In solution, the same reduced steric bulk renders the molecule conformationally flexible, and there is little barrier to rotation about the aryl-methylene bonds. Acknowledgements: the National Institutes
We thank Jorge L. Rios for assistance in the X-ray diffractometry experiment and of Health for financial support to J. C. Phelan through Training Grant GM07273. References
1. 2. 3. 4. 5. 6.
7. 8.
9.
10.
and Notes
For a comprehensive review of all aspects of calixarene chemistry, see: Gutsche, C. D. Culixarenes, Royal Society of Chemis Cambridge, 1989. n? 3.1’5~‘9]octacosa-l(25),3,5,7(28),9,11,13(27),15,17,19(26),21,233*7.19* Pentacyclo[l9.3.1.1 dodecaene is the IUPAC name of 4. Goren, A.; Biali, S.E. J. Chem. Sot. Perkin Trans. I 1990, 1484-1487. Diethylchlorophosphate was prepared in situ by reaction of diethylphosphite with CC4: Zwierzak, A. Synthesis 1976, 305-306. Gutsche, C.D.; Iqbal, M.; Stewart, D. J. Org. Chem. 1986,51,742-745. Gutsche, C.D.; Levine, J.A.; Sujeeth, P.K. J. Org. Chem. 1985,50, 5802-5806. tH NMR (300 MHz, CDCls) 6 7.23 (t, J=8.0 Hz, ArH), 7.10 (d, J=8.0 Hz, ArH), 6.72 (s, ArH), 3.87 (s, CH2). 13C NMR (75 MHz, CDCls) 6 141.5 (4’Ar), 129.0, 128.4, 126.8 (3’Ar), 42.0 (CH 2). FTIR (CC4, in cm-‘) 3060 w, 3030 w, 2920 w, 2850 w, 2300 w, 1600 s (Ar), 1440, 1250 s, 1220 s, 1110, 1090, 1070, 1000 s, 980 s. MS (EI) m/e (rel intensity) 360 (25, Mf), 180 (33), 179 (91), 178 (78), 166 (36) 165 (lOtI), 105 (29), 104 (71), 91 (64). HRMS (EI) m/e 360.1874; Calc’d. for C2sH24, 360.1878. Gutsche, C.D. Act. Chem. Res. 1983,16, 161-170. This chair conformation has been previously observed with resorcinol-derived calixarenes having substituents on the bridging methylene groups: Hogberg, A. J. S. J. Am. Chem. Sot, 1980,102,60466050. Minimizations were done with PCMODEL version 4.0 (Serena Software, Bloomington, Indiana 47402-3076), on a Silicon Graphics Personal Iris workstation. The conformational search was done using MODEL Version KS 2.7 (K. Steliou, University of Montreal, and W.C. Still, Columbia University) with the MM2 force field and batch-mode MMX (Y.H. Yuh & N.L. Allinger; adaptation, modifications, and constants by J.J. Gajewski, K.E. Gilbert, J. McKelvey, and W.C. Still) on a DEC VAX 8530 running VMS. In principle, the lack of NMR coalescence might also be caused by the molecule adopting exclusively the 1,3-alternate conformation in solution, a conformation in which the methylene protons are equivalent. (Received in USA 16 July 1991)