448
J . Am. Chem. SOC.1985, 107, 448-455
3460,3340, 3090,3040,2980, 1650, 1510, 1450, 1385, 1365, 1215, 1070, 985, 915, 700 cm-'; E1 mass spectrum, m / e (re1 intensity) 275 (1 1, M'), 244 (22), 234 (48), 216 (30), 190 (S), 145 (21), 131 (38), 91 (loo), 72 (89), 60 (29), 41 (35). Anal. Calcd for C17H25N02: C, 74.14; H, 9.15; N, 5.09. Found: C, 74.42; H, 8.99; N, 5.181 and 12r [3.2% yield; mp 94.5-95.5 OC from n-hexane/EtOAc; -7.02 (c 5.34, CHCI,); 'H NMR 6 0.63 (d, J = 7 Hz, 3 H), 0.70 (d, J = 7 Hz, 3 H), 1.43-1.80 (m, 1 H), 2.10-2.45 (m, 3 H), 2.61 (br s, OH, 1 H), 2.70-3.14 (m, 2 H), 3.40-3.73 (m, 3 H), 4.90-5.25 (m, 2 H), 5.25-5.50 (m, NH, 1 H), 5.54-6.07 (m, 1 H), 7.0-7.5 (m, 5 H); IR (CCI4) 3450, 3090, 3040, 3010, 2980, 1650, 1595, 1500, 1450, 1375, 1355, 1240, 1070, 985, 910, 800, 695 cm-'; E1 mass spectrum m / e (re1 intensity) 275 (7, M'), 244 (20), 234 (46), 216 ( l l ) , 190 (S), 145 (18), 131 (38), 91 (97), 72 (loo), 60 (36), 43 (30), 41 (45). Anal. Calcd for CI7HzsNO2:C, 74.14; H, 9.15; N, 5.09. Found: C, 74.19; H, 9.06; N, 4.971. A recrystallized sample of 12s was subjected to single-crystal X-ray diffraction analysis. Compound 12s crystallizes from n-hexane/EtOAc in the orthorhombic space group, P212121.The crystal data at 140 K are as follows: a = 5.054 (2) A, 6 = 20.342 (8) A, c = 16.170 (6) A; p(calcd) = 1.10 g for Z = 4; 2B(max) = 50'; 2466 reflections with F > 6u(14) used, Mo K a (graphite (A = 0.71069 A), and w scan, 20' min-'; R = 0.045. SHELXTL programs were used on a DGC Eclipse S/230 computer.
Registry No. la, 93684-28-7; Ib, 93684-29-8; IC, 93684-30-1; Id, 93684-31-2; l e , 93684-32-3; If, 93684-33-4; Ig, 93714-43-3; l h , 93684-34-5; 2a, 93684-35-6; 2b, 93684-36-7; Zc, 93684-37-8; 2d, 93684-38-9; 2e, 93684-39-0; 2f, 93684-40-3; 2g, 93684-41-4; 2h, 88362-53-2; 4c, 93780-03-1; 4h, 63527-49-1; 5a, 93684-42-5; 5b, 93684-43-6; Sc, 93684-44-7; 5d, 93684-45-8; 5e, 93684-46-9; 5f, 9368447-0; Sg, 93684-48-1; Sh, 88362-45-2; 6a, 93684-50-5; 6b, 93684-52-7; 6c, 93684-54-9; 6d, 93684-56-1; 6e, 93684-58-3; 6f, 93684-60-7; 6g, 93684-62-9; 6h, 88362-48-5; 7a, 93684-63-0; 7b, 93684-64-1; 7c, 93684-65-2; 7d, 93684-66-3; 7e, 93684-67-4; 7f, 93684-68-5; 7g, 93684-69-6; 7h, 88362-54-3; 8, 93684-70-9; IOC, 93780-04-2; 10h, 20626-61-3; l l r , 93714-44-4; I l s , 93714-45-5; 12s, 93684-71-0; 121, 93780-05-3; 2-amino- 1-butanol, 13054-87-0; 0-aminobenzenepropanol, 1795-98-8; L-valinol, 2026-48-4; (S)-2-amino-3,3-dimethyl-l-butanol, 93684-72-1; 0-aminobenzeneethanol, 7 1006-16-1;benzenepropionic acid, 501-52-0; propionic acid, 79-09-4; @&dimethylbenzenepropionic acid, 1010-48-6; ethyl propanimidate hydrochloride, 40546-35-8; isobutyric acid, 79-31-2; (S)-(-)-4,5-dihydro-2,4-bis(l-methylethyl)oxazole, 93684-73-2; (S)-(-)-4,5-dihydro-2,4-bis(l-methylethyl)-3-(2-propenyl)oxazolinium 4-methylbenzenesulfonate, 93684-75-4.
Acknowledgment is made to the Committee on Research of the University of California, Davis, the Cancer Research Coordinating Committee, University of California, and to the donors of the Petroleum Research Fund, administered by the American Chemical Society, for the support of this research. We gratefully acknowledge IBM Instruments for the donation of an LC/9533
Supplementary Material Available: A stereoplot of 12s, listings of bond distances, bond angles, hydrogen atom coordinates, isotropic, and anisotropic temperature factors, and observed and calculated structure factors (18 pages). Ordering information is given on any current masthead page.
ternary high-pressure liquid chromatography system.
Host-Guest Complexation. 34. Bridged Hemispherands192 George M. Lein and Donald J. Cram* Contribution from the Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles. California 90024. Received July 13, 1984
Abstract: The synthesis and binding properties of 11 new hemispherands (2-12) are reported, 7 of which contain extra bridges that help preorganize the systems for complexation. These hosts are composed of the following units bonded to one another in 18-membered ring systems: 2,6-disubstituted 4-methylanisyl; 2,6-disubstituted 4-methylphenol; 2,6-disubstituted 4methyl-1-(a1lyloxy)benzene; 6-aryl-substituted 4-methyl-1-methoxybenzene; 2,6-disubstituted pyridine; and pyridine oxide, ethylene, methylene, and oxygen. Association constants (K,)between host and guest to give complexes were determined by extracting picrate salts (guests) from D 2 0 into CDCI3 in the absence and presence of hosts at 25 OC. The rates of extraction were essentially instantaneous. The free energies of complexation for the 11 new hosts with picrate salts of Li', Na', K+, Rb', Cs', NH4+, CH3NH3+,and t-BuNH3+ were determined. These -AGO values ranged from a high of 14.6 kcal mol-' to a low of -2.8 kcal mol-'. Interesting structural recognition factors (KaG/KaG')for a host distinguishing between two similar guests (G and G') are Na+/Li+ = 9500 (8), Na+/K+ = 14 (9),K+/Na+ = 9 (7),K+/Rb+ = 54 ( I l ) , Rb+/Cs+ = 55 (6), NH4+/CH3NH3+= 31 (IO), and CH3NH3+/t-BuNH3+= 40 (10). The strongest binding host for all ions is 12, which gave a -AGO,, for the eight ions of 12.5 kcal mol-'. It is also the most rigid and least discriminating of the hosts. Correlations between the structures of the complexes and their free energies of binding are interpreted in terms of the principles of complementarity and preorganization.
Hemispherands are host compounds, a t least half of whose binding sites are conformationally organized for binding during their synthesis, rather than during their complexation. In other words, hemispherands are at least half preorganized for binding. The synthesis and complexing properties have been previously reported for several members of this class of hosts for which This compound is composed of three compound 1 is pr~totypical.~ self-organizing anisyl units combined with three additional
Chart I
B
-CH2-
(1) We warmly thank the Division of Basic Energy Sciences,Department of Energy (DOE EY 76-S-03-0034,P.A. 218). for a contract that supported this research. (2) The binding free energies of compounds 1,4, and 8 have appeared in a communication: Cram, D. J.; Dicker, I. B.; Lein, G. M.; Knobler, C. B.; Trueblood, K. N. J . Am. Chem. SOC.1982, 104, 6827-6828. (3) Koenig, K.; Lein, G. M.; Stuckler, P.; Kaneda, T.; Cram, D. J. J . Am. Chem. SOC.1919, 101, 3553-3566. 0002-7863/85/ 1507-0448$01.50/0
1 0 PY
P Y0
E
M
CH,0CH2 binding sites. Other hemispherands have been reported that contain four anisyl units4 or anisyl and cyclic urea unit^.^,^ 0 1985 American Chemical Society
Bridged Hemispherands
J . Am. Chem. SOC.,Vol. 107, No. 2, 1985 449
Here we report the synthesis and binding properties of new hosts 2-12, each of which contains a terphenyl molecular module attached to three binding OR groups or two OR and one O H groups. Each host is part of an 18-membered ring system containing three additional binding sites. Seven of the 11 new cycles contain an additional bridge which increases the degree of preorganization of the hosts. With certain complexing partners, preorganization enhances, and with others, preorganization inhibits complexation. In some systems the extra bridge also contains extra binding sites. These compounds were designed and prepared to extend our correlations of structure with binding properties toward alkali metal, ammonium, and alkylammonium ions.’s8 Because of the complexity of the systematic names of these compounds, they are conveniently referred to in-line formulas in which letters identify the units, and their orders of appearance in the line formulas identify their bonding patterns. Chart I identifies the letters with the structures of the units. Chart I1 provides the structures formulas of hosts 1-12 and their associated line formulas.
Results Syntheses. In a synthesis of 1 superior to one that has been (13) was methylated with 1 M equiv of r e p ~ r t e d HAhAhAhH ,~ K2CO3 and excess CH31in acetone to give HAhAAhH (17), which without characterization was hydroxymethylated with KOH(CH,O),-i-PrOH-H,O to provide HOMAhAAhMOH (18,49% based on 13). Methylation of the two phenolic hydroxyls of this compound ((CH3),S0,-K,C03-acetone) gave HOMAAAMOH (16, 96%). Similarly, HAhAhAhH (13) was allylated with CH2=CHCH2Br-K2C03 to provide HAhAaAhH (19), which in turn was hydroxymethylated to give HOMAhAaAhMOH (20, 54% based on 13). Methylation of the two phenolic hydroxyls of this tetrol with (CH3),S04-THF-NaOH led to HOMAAaAM O H (21, 63%). Key intermediate HOMAhAaAhMOH (20) was bridged under high dilution conditions in (CH2),0-2% H,O-NaOH with 0(CH2CH20Ts), to give HOMB[Aa] [EOEIBMOH (22, 51%), with Br(CH2)3Br-KI to produce HOMB[Aa] [ M J B M O H (23, 42%),with Br(CH,),Br-KI to provide HOMB[Aa] [M,]BMOH (24,49%),with Br(CH,),Br-KI to give HOMB[Aa] [MS]BMOH (25, 51%), and with BrCH2PyCH2Br9 to produce HOMB[Aa][MPyM]BMOH (26, 69%). The greater acidity of the phenolic over the benzylic hydroxyl groups of HOMAhAaAhMOH (20) allowed the phenoxide anions to dominante these base-catalyzed substitution reactions, leaving the hydroxymethylene groups intact. The five cyclic diols 22-26 were converted to their corresponding dibromides, 27-31, by treatment with PBr,-C,H, in 50-79% yields. Likewise, open-chain diols HOMAAAMOH (16) and HOMAAaAMOH (21) were converted to BrMAAAMBr (32, 63%) and BrMAAaAMBr (33, 59%),respectively. Macrocyclic hosts 1, 2, 4, 6, and 9-12 were prepared by the slow addition of a solution of the appropriate dibromide (32, 33, 27, 29, 30, or 31) mixed in T H F with either diethylene glycol or pyrido-2,6-dimethano1]0 to a refluxing suspension of NaH-THF using a reflux-return high-dilution apparatus. The products were produced in the following yields: A(AMOE),O ( l ) , 49%;Aa(AMOE),O (2), 33%; A(AMOM),Py (4), 27%; B[Aa] [EOEI[(MOE),O]B ( 6 ) , 21%; B[Aa][M4][(MOE)20]B(9), 33%; B[Aa][M,][(MOE),O]B (lo), 25%; B[Aa][EOE][(MOM),Py]B ( l l ) , 21%; and B[Aa][MPyM][(MOE),O]B (12,4%). The yield ~
~~
~~~~
(4) Artz, S. P.; Cram, D. J. J. Am. Chem. SOC.1984, 106, 2160-2171. (5) Katz, H. E.; Cram, D. J. J . Am. Chem. SOC.1984, 106, 4977-4987. (6) Cram, D. J.; Dicker, I . B.; Lauer, M.; Knobler, C. B.; Trueblood, K. N . J . Am. Chem.Soc. 1984, 106, 7150-7167. (7) Cram, D. J.; Trueblood, K. N . Top. Curr. Chem. 1981, 43-106. (8) Cram, D. J. ‘Proceedings of XVIII Solvay Conference in Chemistry on Design and Synthesis of Organic Molecules Based on Molecular Recognition”, Wiley-Interscience: New York, in press. (9) Newcomb, M.; Timko, J. M.; Walba, D. M.; Cram, D. J. J . Am. Chem. SOC.1977, 99, 6392-6398. ( I O ) Baker, W.; Buggle, K. M.; McOmie, J. F. W.; Watkins, D. A. M. J . Chem. SOC.1958, 3594-3603.
Chart I1
Cn,
12, 17,
._ 15, R =
R = R ’ = H, HAhAhAhH
14, R
R
=
R ’ = CH3, HAAAH
C02H,
H02CAAAC02H
16, R = CPZOH, H O W A M O H
= H, R ’ = CH3, HAhAAhH
19, R = H. R ’ = CH2=CHCH2, HAhAdAhH
En,
IH,
IS, R =
H, R
20. R = H , R 2 1 , R = CH3. ._
= CH3, HOMAhAAhMOH = CH2=CHCH2,
HOMAhAaAhMOH
R ’ = CHZ=CHCH2, HOWAaAMOH
??, 2.3,
X = OH, R = ( C H 2 C H 2 1 p . HOMB[Pa][EOE]BMOH OH, R = ( C H 2 ) 3 .
X
__
2 4 , X = OH, R =
g:,
(CH2)4,
HOMB[Aal[M3]BMOH HOMB[Aa][M,]BMOH
X = OH, R = ( C H z ) 5 , HOMB[Aa][M5]BMOH
26, X = O H , R = CH2PyCH2,
?!. X 2.8, X
= Br, R = (CH2CH2j20, =
HQMB[Aa][HPyM]BMOH Br*IB[Aa][EOE]BMBr
Br, R = ( C H 2 ) 3 , B r M B [ A a l [ M 3 1 B M B r
29, X = Br, R = ( C H 2 i 4 , B m B [ A a l [ M 4 1 B M B r
32. R
= CH3,
!O,
Y =
__3 1 ,
X = Br, R = CH2PyCHZ. B r P I B [ A a l [ M P y M l B M B r
Br, R =
(CH2)5, BrMB[Aal[M5]BMBr
BrMbAAMBr
33, R = CH2=CHCH2, B M a A H B r
of A(AMOE),O (1) produced by this method (49%)was superior to the 35% obtained through the reaction of HOMAAAMOH (16) with O(CH,CH,OTS),.~ Attempts to prepare B[Aa] [M,] [(MOE),O]B from BrMB[Aa] [M3]BMBr (28) and diethylene glycol or from HOMB[Aa] [M3]BMOH (23) and O(CH,CH,OTS)~failed to give isolable amounts of host. Serious attempts to obtain the 15-membered host A(AMO),E by the reaction of BrMAAAMBr (32) with H O C H 2 C H 2 0 H failed.
Lein and Cram
450 J . Am. Chem. SOC.,Vol. 107, No. 2, 1985
Table I. Association Constants ( K , ) and Binding Free Energies (-AGO) of Hosts for Picrate Salts in CDCl, Saturated with D 2 0 at 25 OC
host structure
no.
Na'
Rb'
K+
cs+
-AGO" for Guest Cation, kcal mol-' 1 1.8'3' 10.4 9.0 1 1 .3' 9.5 7.8 8.0 6.8 6.5 10.9c 9.0 7.8 12.9' 11.4 9.0
4 6
7.0 6.9 6.5 7.4 7.5
12.2'9' 12.0c 7.9 12.0' 12.5
