J. Am. Chem. SOC.1991, 113, 5707-5714 Mechanism of Oxygen Rebound, The detailed mechanism of hydroxylation of carbon-centered radicals (reaction 3) has generally been either ignored or considered to be a combination of the carbon-centered radical with a hydroxyl radical.g2 The latter mechanism implies that the iron-oxygen bond in the hydroxyferryl species must undergo thermal cleavage before hydroxylation can occur. This is, of course, improbable both on energetic grounds and because an enzyme which generated a free hydroxyl radical would not survive for long. Furthermore, the reaction of an alkyl radical with a free hydroxyl radical would be expected to yield disproportionation products, Le., alkene and water as well as the alcohol combination product. In the case of hexamethylcyclopropane we have shown that olefin is not produced, and hence we rule out the production of a free hydroxyl radical. The actual hydroxylation step most probably involves a bimolecular homolytic s ~ b s t i t u t i o n(SH2) ~ ~ at oxygen of carbon for iron?’ Le., reaction 24. W e cannot rule out, but see no reason 1-
-c;
LG” \
/ \ +
\ -C-OH
(24)
/
\Fe”’/
/ \ +
to invoke. a direct interaction between the carbon-centered radical (92) For example?) “attack of this iron-oxo species on the substrate molecule through hydrogen abstraction followed by radical recombination to generate the alcohol product”. (93) Murray, R. 1.; Fisher, M.T.; Debrunner, P. G.; Sligar, S.G. Topics in Molecular and Srrucrural Biology 1985,6, 157-206. See: p 191. (94) Roberts, B. P.;Ingold, K.U. Free-Radical Subsrirurion Reactions; Wiley-Interscience: New York, 1971. (95) Champion, P. M. J . Am. Chem. SOC.1989, 1 1 1 , 3433-3434.
5107
and the iron atom to form an FeV species; Le., we see no reason to invoke an intermediate with a carbon-iron bond, particularly in such a “crowded” local environment. Finally, in all cases where there is no clear evidence for the intermediate formation of carbon-centered radicals, it must not be forgotten that an oxene insertion mechanism may be in operation.
Acknowledgment. We thank Dr. D. 0. Foster for preparation of the P-450 microsomes, D. A. Lindsay for his valuable technical assistance, E. Lusztyk for a second, extremely careful examination of the products formed from the P-450-catalyzed oxidation of leH, and the Association for International Cancer Research and the National Foundation for Cancer Research for partial support of this work. W e also thank Prof. J. Warkentin for generously providing a sample of 3-methoxy-3,5,5-trimethyl-4-oxa-lpyrazoline and two referees for some very useful suggestions. Registry No. laH, 594-11-6; laOH, 2516-33-8; la’, 2154-76-9; lbH, 2402-06-4; IbOH, 21003-36-1; lb’, 62131-99-1; lcH, 930-18-7; IcOH, 21003-35-0; IC’, 62131-98-0; ldH, 1630-94-0; ldOH, 2746-14-7; Id’, 24389-71-7; leH, 4127-47-3; leOH, 133753-26-1; le’, 133753-28-3; IM, 2570-81-2; IfOH, 133753-27-2; I f , 133753-29-4; lkH, 24518-94-3; IIH, 1667-00-1; llOH, 1007-03-0; ll’, 126281-30-9; Za’, 2154-62-3; Zb’, 51685-66-6; ZbOH, 24389-75-1; ZeOH, 19781-53-4; Ze’, 50517-76-5; ZfOH, 4819-92-5; Z f , 133753-31-8; ZIOH, 937-58-6; 21’, 133753-32-9; 3bOH, 4516-90-9; 3b’,52898-42-7; M H , 3329-43-9; W,133753-30-7; 4H, 185-94-4; d24H, 51794-28-6; 4 0 H , 24461-57-2; 4’, 84592-00-7; 5 0 H , 14320-38-8; 9,14461-09-7; cytochrome P-450, 9035-51-2; monooxygenase, 9038-14-6; 2-butyn-1-01, 764-01-2; ethyl dimethylaceto35293-39- 1 ; methyl acetate, 597-04-6; ethyl 2,2,3-trimethyl-3-butenoate, 1,2,2-trimethylcyclopropanecarboxylate,20459-94-3; 3-methoxy-3,5,5trimethyl-4-oxa-l-pyrazoline, 77879-49-3; 4-phenyl-3-butenoic acid, 2243-53-0.
Vases and Kites as Cavitands’ John R. Moran, John L. Ericson, Enrico Dalcanale, Judi A. Bryant, Carolyn B. Knobler, and Donald J. Cram* Contribution from the Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90024. Received December 3, 1990
Abstract: The syntheses, characterizations, and substituent effects on the vase vs kite conformations of 1-17 are described. These compounds are assembled by two-step syntheses from resorcinol (or 2-substituted derivatives) and aldehydes to form octols 18-26 in high yields, followed by 4-fold bridging reactions with quinoxalines 27-29 or pyrazine 30. In the crystal structure of 3.2CH2CI2, one CH2Clz is enclosed in the vase cavity, while a second CHzC12is found surrounded by the four (CHZ)&I groups. When the 2-position of resorcinol is hydrogen, only the vase form of the cavitands exists at 25 OC or higher when quinoxaline bridged, as in 1-7, and at all available temperatures when pyrazine bridged, as in 13. The R and B groups of 1-7 can be varied to control solubility and cavity size without greatly affecting the vase-kite structures. When the 2-position of resorcinol is occupied by a methyl, an ethyl, or a bromine, as in 14-17, only the kite conformation is observed at all available temperatures. When the 2-position is hydrogen and the system is quinoxaline, only the kite conformer is observed at temperatures below -50 OC. When the 2-position is CH3, the kite conformer equilibrates with its dimer. When the 2-position is CH3CH2, as in 17, the kite conformer does not form a dimer. The kite C, structures under pseudorotation and also dimerize when they contain 2-methylresorcinyl groups to give dimers of Du symmetry. In some systems, these processes could be differentiated by use of variable-temperature IH NMR spectra.
In an earlier paper,2 we described the preparation and equilibration of the vase (four quinoxaline flaps axial, or aaaa conformation) and kite (four quinoxaline flaps equatorial, or eeee conformation) structures for 1. Compound 1was reported to form crystalline solvates that were stable to moderate heat and vacuum, ( I ) (a) We warmly thank the National Science Foundation for Grant CHE 88-02800, which supported this work. (b) Host-Guest Complexation. 57. (2) Moran, J. R.;Karbach, S.;Cram, D. J. J . Am. Chem. Soc. 1982, 104, 5826-5828.
which suggested the solvent molecules occupied the sizable cavity as guests of 1. In a later paper, Vincenti, Dalcanale, Soncini, and Guglielmetti found that an analogue of 1 (R = CsH13)bound guest molecules strongly in the gas phase.3 Our paper reports the following: (1) the syntheses of cavitands 1-17 and 31 and octols 21 and 25; (2) the crystal structure of the vase form of 3.2CH2C12; and (3) the results of an investigation of the effects of substituents (3) Vincenti. M.; Dalcanale, E.; Soncini, P.; Guglielmetti, G. J. Am. Chem. SOC. 1990, 112, 445-447.
0002-7863/91/1513-5707$02.50/0 0 1991 American Chemical Society
5108 J . Am. Chem. Soc., Vol. 113, No. 15, 1991
Moran et al.
R, A, and B and of solvent on the vase vs kite vs dimer-kite structures. 100-
Kite
c.L*ED,
Vase 14-
50 -
T
("C) 0 -
I
.
I\
-50Vase, or aaaa conformer
Kile, or eeee wnformer
8. R = A = CH3, B = H 9. R = A = B = CH2
5.5
5.0
4.0
4.5
PPM (8) Figure 1. Effect of temperature changes in the chemical shifts of H' protons (5OcbMHz 'HNMR spectra) of 1,13, and 14 in various solvents.
Vase IWt)
Me
13
14. A = R = CH3 15, A = B r , R = CH3 16, A = CH3. R = (CH214CH3
of 4 mol of the appropriate aldehyde with 4 mol of resorcinol (or 2-methylre~orcinol)~ catalyzed by acid. Octo1 18 was also brominated to give 24.2 Only the diastereomer drawn was isolated. The yields ranged from 60-95%, and the dominant conformer in each case is the one f ~ r m u l a t e d .In ~ the present work, octo1 21 was similarly prepared from 2-methylresorcinol and 6-chlorohexanal (65%) and 25 from 2-ethylresorcinols and hexanal (87%). The octols were converted to cavitands by treatment with 2,3-dichloro- 1,Cdiazines 27-30, whose chlorines are good leaving groups for nucleophilic aromatic substitution reactions. Of these bridging aromatic reagents, only 27 was commercially available. Quinoxalines 28 and 29 were prepared as before,6 and pyrazine 307awas prepared as well. In general, reactivity decreases for each chlorine displaced, while alkoxy and phenoxy grou s substituted for C1 in 30 appear to direct substitution ortho.' The strong fluorescence of the cavitands facilitated isolation of the desired products. The bridging of the four sets of hydrogen-bonded hydroxyls by the reaction of octols with 4 mol of diazines produces four new nine-membered rings (eight bonds broken and made). The reactions were best conducted in dry, aprotic, dipolar solvents with K2CO3, CsHCO,, or Cs2C03as bases. The highest yields were observed when CsHC03 or Cs2C03were used in (CH3)2S0or (CH3)2NCOCH3,which provides another example of Kellogg's 'cesium effect".8 For example, the reaction 18 4 27 1 went in 34% yield with KOH-(CH,),NCHO, but in 83% with Cs2C03-(CH3)2S0.The synthesis of 1, when conducted in dry (CH3)2SO-CsHC03with 3 equiv of 27 for 2 days a t 25 OC, gave a mixture of 1 (30%) and 31 (40%), which was easily separated. Thus, it appears that the first three bridges are formed faster than the fourth, probably for steric reasons. This observation provides an easy means of synthesizing cavitands with two different kinds of bridges3 in the same molecule. The cesium effect seems to apply generally to the other systems as well. In the syntheses of 2 (37%), 3 (40%), 10 (30%), 11 (30%), 16 (16%), and 17 (32%), K2C03-(CH3),NCH0 was employed, whereas in those of 8 (77%) and 9 (68%) (CH3)2SO-Cs2C03) was used. In the preparation of 13 (75%), 14 (SO%), and 15 (1%), (CH3)2NCOCH3-Cs2C03 served as solvent-base. The low yield in the last reaction is attributed to the steric effect of the bromines ortho to the hydroxyls. Tetraiodides 4 and 12 were obtained (85% each) by heating the respective chlorides 3 and 11 with NaI in refluxing 2-butanone.
!
I7b
17a
)@$I:: -
27. B = H 28. B = CH3 Br
29. B
--- -
-
18 R - C H 3 A - H 19: R = ( C H h 2 H 3 , A = H 20 R (CH2)sCI A H 21' R (CH2)SCI'A = CH3 22: R = CH2cH(&3)2. A = H 23. R A CH3 24, R CH3.A = Br 25 R = (CH2)4CH3. A = CH2CH3 26: R = (CH214CH3. A = CH3
30
31
Results and Discussion Syntheses. In a previous paper, we reported the syntheses and characterizations of octols 18-20,22,23, and 26' by condensation ~~
(4) Tunstad, L. M.; Tucker, J. A.; Dalcanale, E.; Weiser, J.; Bryant, J. A.; Sherman, J. C.; Helgeson, R. C.; Knobler, C. 8.;Cram, D. J. J . Org. Chem. 1989,54, 1305-1312.
+
-
(5) Limaye, D. B.; Ghate, I. Rasmayanam 1936, I , 39-42. (6) Checseman, G. W. H.; Cookson, R. F . Condensed Pyrazines; John Wiley: New York, 1979; Vol. 35, pp 162-178. (7) (a) Allison, C. G.; Chambers, R. D.; Macbride, J. A. H.; Musgrave, W. K . R. J . Chem. Soc., C 1970, 1023-1029. (b) Cheeseman, G. H.; Werstiuk, E. S.G . Adu. Heterocycl. Chem. 1972, 14, 99-209. (c) Chambers, R. D.; Musgrave, W. K. R.; Urben, P. G . J . Chem. Soc., Perkin Trans. I , 1974, 2584-2589, 1972, 2190-2192. (8) Piepers, D.; Kellogg, R. M. J . Chem. Soc., Chem. Commun. 1978, 383-384.
J . Am. Chem. SOC.,Vol. 113, No. 15, 1991 5709
Vases and Kites as Cavitands
3*2CH2C12
Stereoview 32 of 302CH2C12, with 0's and Cl's darkened.
Crystal Structure of 3.2CH2CI2. The crystal structure of 3. 2CH2CI2was determined and refined to give an R value of 0.13. Stereoview 32 shows that the compound is in a vase conformation whose upper and lower cavities each contain one molecule of CH2CI2. The host possesses approximate C , symmetry, with the guests' C H I groups lying close to the C4axis. The bottom part of the upper cavity is lined with the four resorcinyl units sloping inward a t the bottom. The middle and upper parts of the cavity are lined with the four quinoxaline units arranged as if their faces were the sides of a box. However, these planes are tilted an average of 6O inward a t their tops so that their attached 6- and 9-hydrogen atoms essentially touch one another. The eight ether oxygens are arranged with their unshared electron pairs facing outward. The crystal structure of the host corresponds closely to that observed in CPK molecular models of the host, the upper cavity of which is rigid and apparently strain-free. In models, the cavity is much larger than the CH2CI2 guest. A molecular model of [2.2]paracyclophane (inner faces shaved) shows it just about occupies the interior of the cavity of a model of 1. The two cavities of crystal structure 32 closely resemble that of the analogue of 1, in which A = (CH2)SCH3and B = H , which we will call 33 (Dalcanale et al.).9 This compound, when crystallized from acetone, gave 3 3 ~ 3 ( C H ~ ) ~(not C 0 formulated), whose upper cavity contained two acetone molecules (one fully enclosed, and one slightly enclosed) and whose lower cavity contained 1 mol of acetone fully enclosed by the four hexyl groups. The close similarities between 32.2CH2CI2 and 33.3(CH3)2C0 on the one hand and CPK models of the two complexes on the other add to the growing number of examples in which predictions based on CPK models about the structures of highly preorganized hosts have been verified by crystal structure determination.I0 Vase and Kite F o m of Cavitands 1,5,6, and 13. The IH NMR spectra of cavitands taken in different solvents and a t different temperatures proved useful in identifying the structures of the vase vs the kite conformers, of the monomer vs dimer forms of the kite conformers, the degeneracy of the kite monomers, the substituent effects on the stabilities of all forms, and the activation free energies for their interconversions. Fortunately, the substituent effects, both steric and electronic, were large enough in certain cases to allow the spectra of single species to be taken and related to crystal structures and CPK models of the same species. Crystal structures have been determined for the vase form of 32CH2CI2and of 333(CH3)2C0,9the monomer form of kite 17," the dimer-kite form of 10,llaand of the dimer-kite form of 16.Ilb Cavitand 1 in 1:l CDCI,-CS2 (v/v) appears to exist only in the vase form a t temperatures of 45 OC and above and only in the kite form at temperatures below -62 OC. In the 500-MHz IH N M R spectrum of 1 from 45-70 OC, all protons exhibit sharp (9) Dalcanale, E.; Soncini, P.; Bacchilega, G.; Ugozzoli, F. J . Chem. Soc., Chem. Commun. 1989, 500-502. (IO) Cram, D. J . Chemtracrs 1988, 1, 89-101. (11) (a) Bryant, J . A.; Knobler, C. B.; Cram, D. J. J . Am. Chem. Soc. 1990, 112, 1255. (b) Bryant, J . A,; Ericson, J . L.; Knoblcr, C. B.; Cram, D. J. Unpublished results.
signals consistent with C , symmetry. The H a signal changed dramatically and continuously as the temperature was lowered from 45 to - 6 2 O C , but changed little from - 6 2 to -72 O C (Figure 1). The signals at intermediate temperatures are broad and show coalescence a t about -5 OC. The well-defined methine quartet (Ha) moves from 6 5.67 at 45 O C to 6 3.92 at - 6 2 OC (A6 = 1.75) and broadens. The AG* for the conformational changes involved is about 11.6 kcal mol-'.12 The two benzene proton singlets a t 8.04 ( H b ) and 7.27 (HC) at 45 OC shift much less when the temperature is lowered to 62 OC, and each of these divides into two singlets found a t 6 7.38 and 7.28 and a t 7.21 and 6.41, respectively. The protons of the quinoxaline ring a t 45 OC exhibit a symmetrical AA'BB' splitting pattern, which at - 6 2 OC divided into two doublets and two triplets interpreted as an ABCD spectrum. Thus, the spectrum from -SOo to - 6 2 OC is consistent with a structure of C , symmetry." These spectra, coupled with the crystal structure of 3 (see 32) and CPK model examinations of the vase and kite forms of 1, correlate to provide the following interpretations: (1) The 45-70 O C spectrum is explained by 1 assuming the vase (aaaa) conformation, which has C , symmetry. In this structure, the Ha methine protons are relatively distant from the faces of the quinoxaline ring and at 6 5.67 are at lower field than the methines of the rigid C,, model compound 34 (4.96).14 (2) The -62 to Hb
34
-72 OC spectrum is explained by 1 having the kite (eeee) conformation (C2, symmetry). The A6 = 1.75 upfield shift of the methine H a signal from 6 5.67 to 3.92 as the temperature is lowered correlates with the methine protons moving into the shielding cone of the quinoxaline rings as the latter occupy the e positions. (3) Although all protons exhibit shifts between 45 and -62 OC, their signals do not change above 45 and below - 6 2 OC. The spectra above 45 OC show no detectable (
