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Enantioselective Complexation of Chiral Dicarboxylic Acids in Clefts of Functionalized 9 9-Spirobifluorenes.

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[9] A. Simon, H. J. Deiseroth, Rev. Chim. Miner. 1976, 13, 98.
[lo] The Ba,N chams correspond to those reported in Cs,O [ll], but there is
some doubt about the correctness of the reported structure [12]. Crystals
of Cs,O exhibit strong diffuse superstructure reflections not taken into
account in the reported structure [13]. The diffraction pattern of NaBa,N
is free of any such diffuse reflections.
[ l l ] K.-H. Tsdi, P. M. Harris, E. N. Lassettre, J. Phw. Chem. 1956, 60. 338.
[12] A. Simon, 2. Anorg. Allg. Chem. 1973, 395, 301.
[13] F. Okino, A. Simon, unpublished results, 1985.
[14] A. Simon, W. Bramer, H. J. Deiseroth, Inorg. Chem. 1978. 17, 875.
[151 S. M . Ariya, E. A. Prokofyeva, I . I. Matveeva, J. Gen. Chem. U S S R 1955,
26. 609.
[16] A. Slmon, Angrn. Chem. 1988,100,163:Angew. Chem. In/. Ed. EngI. 1988,
27. 159.
[17] H. Schafer. H. G. von Schnering, J. Tillack, F. Kuhnen, H. Wohrle, H.
Baumann. Z. Anorg. Allg. Chem. 1967, 353, 281.
[18] A. Simon, H. G. von Schnering, H. Wohrle. H. Schafer, Z. Anorg. A&.
('hem. 1965. 339, 155.
[I91 D. Adolphson, J. D. Corbett, Inorg. Chem. 1976, 15, 1820.
(201 M. Potel, R. Chevrel, M. Sergent, Acru Crysluffogr. Secl. B1980,36. 1545.
(211 A. Simon, Z. Anorg. Allg. Chem. 1967, 355, 311.
[22] R. P. Ziebarth, J. D. Corhett. J. Solid State Chem. 1989,80, 56.
[23] H. Mattausch, W. Schramm, R. Eger, A. Simon, Z. Anorg. Allg. Chem.
1985. 530. 43.
[24] A. Simon, .I Solid S / u & Chem. 1985, 57, 2; S. M. Kauzlarich, T. Hughbanks. J. D. Corbett, P. Klavins. R. N. Shelton, Inorg. Chem. 1988, 27,
[25] M. E. Badding. F. J. DiSalvo, Inorg. Chem. 1990. 29, 3952.
For the preparation of (R)- and (S)-1,the racemic dicarboxylic acid 3 was prepared according to Prelog et al. and
optically resolved via the diastereomeric amides obtained by
reaction of the corresponding acyl halide with ( -)-dehydr~abietylamine.[~~I
The conversion of the acyl halides, prepared from (R)-(+)- and (S)-(-)-3,["1 with 2-amino-6methylpyridine afforded the enantiopure receptors (R)-1
([a];2 + 177.5 (c = 0.435 in CHCI,) and (S)-1 ([M]:'
(c = 0.570 in CHCI,)). The optically active amino acid
derivatives needed as substrates for the binding studies were
either commercially available or were prepared according to
routine procedures.["] The optically active 2,2'.7,7'-tetrasubstituted spirobifluorene (S)-4 ([a]:& +3.1 (c = 0.450 in
acetone)) was obtained by acylation of (S)-3(C,H,,COCI,
AICI,, CS,, 67 YOyield).
Enantioselective Complexation of Chiral
Dicarboxylic Acids in Clefts of Functionalized
9,9'-Spirobifluorenes* *
By Victoria Alcazar and FranGois Diederich*
The results of several studies on the enantioselective recognition of chiral substrates by optically active receptors have
led to the conclusion that large differences in stability between diastereomeric complexes are preferentially obtained
when the receptors are conformationally homogenous''. 'I
and when differential oriented bonding interactions, for example hydrogen bonding, are effective in the c ~ m p l e x e s-61
Following these guidelines, we recently prepared the receptors 1 and 2 which incorporate a cleft formed by a rigid
9,9'-spirobifluorene unit functionalized with hydrogenbonding residues. The 9,9'-spirobifluorene unit had previously been introduced by Prelog et al.''] as spacer in chiral
crown ethers. Binding studies with the racemic hosts showed
that 1, but not 2, was capable of forming 1 : 1 complexes with
aliphatic and aromatic dicarboxylic acids in chloroform
(association constants K , z lo3 to lo5 Lmol-' at 293 K).
These complexes are mainly stabilized by hydrogen bonds
between the two COOH groups of the guests and the two
On the other
aminopyridine residues in 1 (Scheme 1 a).[8s9]
hand, monocarboxylic acids form much weaker complexes
(K, z 100 to 400 Lmol-'). In this report, we describe first
investigations of the enantioselective complexation of chiral
dicarboxylic acids by the enantiopure receptors (R)-and ( S ) 1 and compare their chiral recognition potential to that of
similarly functionalized but more flexible 1,l'-binaphthyl
Prof. Dr. F. Diederich, Dr. V. Alcazar
Laboratorium fur Organische Chemie, ETH-Zentrum
Universitatstrasse 16, CH-8092 Zurich (Switzerland)
Department of Chemistry and Biochemistry
University of California
Los Angeles, CA 90024-1569 (USA)
[**I This work was supported in part by the U.S. National Institutes ofHealth
and by the Fulhright Foundation (fellowship for V.A.).
Angew. Chem. Inl. Ed. Engl. 1992, 31, No. 11
0 V C H Verlagsgesellschufi m b H ,
3 R=H
4 R = CH,(CH&CO
Table 1 shows the results of 'HNMR binding titrations
executed under fast-exchange conditions and in significant
concentration ranges.'"] The following findings are of particular interest:
1) The N-protected derivatives 5-8 of the acidic amino
acids L-aspartic acid (L-Asp) and L-glutamic acid (L-G~u)
selectively recognized by the enantiomeric receptors. Differences in stability as high as A(AGo) = 0.9 kcalmol- ' are
measured for the diastereomeric complexes of the N-carbobenzyloxy (Cbz) protected substrates. Interestingly, L - A s ~
and L-GIu prefer binding to different host enantiomers. The
Asp derivatives 5 and 6 form the most stable complexes with
(5')-1, whereas the Glu derivatives 7 and 8 bind strongest to
(R)-1.As a consequence of the different chain length, which
is even-numbered in 5/6 and odd-numbered in 7/8, the terminal carboxyl residues adopt very different orientations in the
complexes, which ultimately leads to an inversion of the
favored host configuration. This explanation is currently
being tested in computer modeling studies.["]
Binding constants of similar magnitude are measured for
the complexes of the Cbz derivatives and the n-butylcarbaW-6940 Weinheim. 1992
3.50+ .25/0
o r
Table 1. Association constants K, and binding free energies -AGO (uncertainty
0.1 kcalmol-') of the diastereomeric complexes formed by the enantiopure
receptors 1 and 12 in CDCI, at 293 K. The value ofA(AG") indicates the difference in stability between diastereomeric complexes.
[kcalmoi- '1
series of control experiments: Compounds l l a - e formed
weaker complexes (K, x 10-700 Lmol-') with binding
strengths similar to those exhibited by complexes with
monocarboxylic acids, and chiral recognition was less effective (Table 1). On the other hand, considerable enantioselectivity was observed in the complexation of the two chiral
succinic acid derivatives 9 and 10.
( 0 1
4 200
4 800
23 000
3 400
20 800
19 400
8 500
7 200
mates. This indicates that the phenyl residues of the Cbz
groups do not have specific stabilizing aromatic interactions
with the spirobifluorene unit. This assumption is further supported by the absence of specific, complexation-induced
changes in the 'HNMR chemical shifts as well as by the
absence of significant intermolecular Nuclear Overhauser
effects in the complexes. For stable complexation and efficient chiral recognition, the presence of two carboxyl
residues in the guest is essential. This is clearly shown in a
Scheme 1. a) Optimal hydrogen-bonding array in the complexes formed by (R)and (S)-1 with dicarboxylic acids, as supported by computer modeling studies
[8a]. b) Hydrogen bonds in the diastereomeric complexes of (R)-and (S)-1 with
2) Whereas complexation has a pronounced effect on the
equilibrium between the cis and trans conformations of the
NH-CO carbamate bond of 5, no such effect is seen with
7.[13]The integration of the NH and C(a)H proton NMR
resonances, which appear at higher field in the truns and at
lower field in the cis c o n f ~ r m a t i o n ~shows
' ~ ] that the cis/
trans ratio of 3 : 1 in the free substrate 5 changes to 8 : 1 in the
two diastereomeric complexes formed with (R)-and (S)-1. In
contrast, the same cisltruns ratio of 8 : 1 is measured for both
free and complexed carbamate 7.
3) A very high enantioselectivity, A(AGo) = 1.8 f
0.1 kcal mol - ', was measured for the complexation of the
(S)-spirobifluorene-2,2'-dicarboxylicacid 4 by (R)-and ( S ) 1. The origin of this large difference in stability becomes
apparent in examinations of CPK molecular models
(Scheme 1 b). Only in the complex of similarly configurated
host and guest are the two spirobifluorene units capable of
assembling in a way to lead to the formation of four hydrogen bonds. In the other diastereomeric complex, the interactions of two COOH groups with the H-bonding functionality of the host are impossible for geometrical reasons.
Therefore, the association constant of the latter complex is
small and of a magnitude characteristic for 1 : 1 complexes of
monocarboxylic acids and amidopyridines. This result suggests that enantiopure host 1 could be prepared by resolving
its direct precursor, the racemic spirobifluorenedicarboxylic
acid 3, through complexation with previously formed optically pure (R)-and (S)-1 followed by crystallization, extraction, or chromatography.
4) The findings with the spirobifluorene receptors (R)(S)-1 are in sharp contrast to the results obtained with the
analogous I ,l'-binaphthyl cleft molecules (R)-12 ([a];'
-19.40 (c =1.01 in CHCI,)) and ( 9 - 1 2 ([a];' +19.28
(c = 1.12 in CHC1,)).[Zb3
8b1 Although substrates 5-8 and the
dicarboxylic acid (R)-13([46z + 14.74 (c = 0.231in CHC1,))
form stable complexes with the binaphthyl receptors, no significant degree of chiral recognition was observed
(Table I).[' 51 In contrast to the rigid spirobifluorene frame,
the binaphthyl unit is conformationally flexible and capable
of adopting geometries which fit both substrate enantiomers.
As a consequence, diastereomeric complexes of similar ener-
0 R
Verlagsgesellschafi mbH, W-6940 Weinheim, 1992
3 3S0+ .2S/O
Angew. Chem. I n f . Ed. Engl. 1992, 3f. N o . I f
gy are formed. However, through careful control of the 1,I/binaphthyl geometry, for example by an additional binding
site in the 2,2'-po~itions,['~~
it should be possible to rigidify
the cleft molecule and enhance its efficiency in chiral recognition. Experiments in this direction are now under way.
Received: June 19,1992 [Z 5433 IE]
German version: Angeu,. Chem. 1992, 104, 1503
CAS Registry numbers:
(R)-1 .(S)-4, 144017-09-4; (R)-1.5, 144017-06-1; (R)-l.6, 144068-54-2;
(R)-l.7, 144068-55-3; (R)-1 '8, 144068-56-4; (R)-1 ' 9 , 144017-07-2; (R)-l. 10,
144017-08-3; ( R ) - l .11 b, 144068-57-5; ( S ) - l .(S)-4, 143957-65-7; (S)-l.5,
143957-58-8; (S)-1 ' 6 , 143968-92-7; (S)-1 '7, 143957-59-9; (S)-1 '8, 14396894-9; (S)-l.9, 143957-61-3; ( S ) - l '10, 143957-63-5; (S)-l.11 b, 144000-09-9;
(R)-12' 7 , 143957-67-9; (R)-12.(R)-13, 143957-71-5; (S)-12.7, 143957-69-1;
( S ) - l 2 .(R)-13, 143957-72-6.
[l] a) R. Liu, P. E. J. Sanderson, W. C. Still, J. Org. Chem. 1990, 55, 51845186; b) .I.-I. Hong, S. K. Namgoong, A. Bernardi, W. C . Still, J. Am.
Chem. Soc. 1991, f13, 5111-5112.
[2] a) T. M. Georgiadis, M. M. Georgiadis, F. Diederich. J. Org. Chem. 1991,
56. 3362-3369; b) P. P. Castro. F. Diederich, Tetrahedron Lett. 1991,32,
6211- 6280.
[3] W. H. Pirkle, T. C. Pochapsky, Chem. Rev. 1989,89, 347-362.
[4] a) K . S. Jeong, A. V. Muehldorf, J. Rehek Jr.,J. Am. Chem. Soc. 1990,112,
6144-6145; b) M. Famulok, K.-S. Jeong, G. Deslongchamps, J. Rebek,
Jr., Angew. Chem. 1991,103,880-882; Angew. Chem. In!. Ed. Engl. 1991,
30. 858-860.
[5] A. Galbn, D. Andreu, A. M. Echavarren, P. Prados. J. de Mendoza, J. Am.
Chem. Soc. 1992, 114, 1511-1512.
161 P. P. Castro, T. M. Georgiadis, F. Diederich, J. Org. Chem. 1989,54,58355838.
(71 a) V. Prelog, Pure Appl. Chem. 1978, 50, 893 -904; b) G. Haas, V. Prelog,
Hrlv. Chim. Acta 1969, 52, 1202-1218; c) V. Prelog, D. Bedekovic, ibid.
1979. 62. 2285-2302; d) V. Prelog, S. Mutak, ihid. 1983, 66, 2274-2278;
e) M. Dobler, M. Dumic, M. Egli, V. Prelog, Angew. Chrm. 1985, 97,
793-794; Angew. Chem. Int. Ed. Engl. 1985, 24, 792-794.
[XI a) V. Alcazar Montero, L. Tomlinson, K. N. Houk, F. Diederich, Tetruhedron Lett. 1991,32, 5309-5312; b) V. Alcazar, J. R. Moran, F. Diederich,
Isr. J. Chem., in press.
[9] F. Garcia-Tellado, S. Goswami, S.-K. Chang, S. I. Geib, A. D. Hamilton,
J. Am. Chrm. Sor. 1990, 112,7393-1394.
[lo] The assignment of the absolute configuration was made according to Prelog et al., see ref. [7c]. All new compounds were completely characterized
by 1R and 'H NMR spectroscopy. mass spectrometry, melting point, and
elemental analysis.
[ l l ] Examples for complexation-induced downfield shifts of the 'H NMR signals of the host in the (R)-1 .7 complex at saturation binding: A6,,, =
+0.24.5 (1-H); f0.057 (3-H); +0.048 (3'-H); f0.116 (4'-H); +0.044
(5'-H); f2.628 (NH). Both the shifts of the aromatic resonances and the
amide protons were evaluated to determine the association constants given
as average values in Table 1.
[I21 L. Tomlinson, K. N. Houk. V. Alcazar. F. Diederich, unpublished results.
[13] C. Vicent, S. C. Hirst, F. Garcia-Tellado, A. D. Hamilton, J. A m . Chem.
Soc. 1991, 113, 5466-5467.
1141 J. L. Dimicoli, M. Ptak. Tetruhedron Lett. 1970, 2013-2016.
[I51 For similar independent findings see: F. Garcia-Tellado, J. Albert, A. D.
Hamilton. J. Chrm. Sor. Chem. Commun. 1991, 1761-1763.
[16] F. Diederich. M. R. Hester, M. A. Uyeki, Angew. Chem. 1988, 100, 17751777: Angew. Chem. In!. Ed. Engl. 1988, 27, 1705-1706.
The Uncatalyzed Transfer Hydrogenation of
a-Methylstyrene by Dihydroanthracene or
Xanthene-a Radical Reaction**
By Christoph Riichardt,* Matthias Gerst,
and Margo1 Nolke
During an investigation of the thermolysis of 3-(l-methyl1-phenylethyl)pentane-2,4-dioneat 290 "C with dihydroanthracene DHA 2 a as a radical trap, we observed that a[*] Prof. C . Rbchardt, Dip).-Chem. M. Gerst, DipLChem. M. Nolke
Institut fur Orgdnische Chemie und Biochemie der Universitat
Albertstrasse 21, D-W-7800 Freiburg (FRG)
Bimolecular Formation of Radicals by Hydrogen Transfer, Part 1 . This
research was supported by the Fonds der Chemischen Industrie.
Angew. Chem. Int. Ed. Engl. 1992, 31, No. I 1
methylstyrene (1) formed initially was hydrogenated to
cumene and that anthracene was an additional product. In
independent experiments it was demonstrated that cc-methylstyrene (1) is hydrogenated by DHA 2a almost quantitatively at 280-310 "C in an uncatalyzed H-transfer reaction.
Hydrogen-transfer reactions between H donors and H acceptors catalyzed by transition metals are well known,['l and
examples catalyzed by Lewis acids have also been described.['l Yet the literature contains few examples of uncatalyzed H-transfer reactions between organic or organometallic H donors and unsaturated hydrocarbons. The
mechanisms of these reactions were either not examined
more closely,[31or they were described as pericyclic synchronous transfer^.'^] For DHA 2a and xanthene (2b) a
pericyclic reaction is not possible, since it either cannot be
formulated or it is symmetry forbidden as a thermal reaction (e.g. the reaction of 1 with 2 a of the type
[,2, + .2, .2, + n4,][4c1).Recently, multistep mechanisms
have been formulated in which bimolecular radical formation proceeds by H t r a n ~ f e r ; [ ~most
- ~ l of the examples concern the assumed initiation steps of radical chains as in the
uncatalyzed polymerization of styrene,Isa' the thermal chain
addition of alkanes to alkene~!~~]
and the thermal decomposition of dihydronaphthalenes[61 and i s ~ t o l u e n e .These
[ ~ ~ re-
20 : X = CH,
2b: X = 0
actions are not suitable for an exact mechanistic study. The
stoichiometric disproportionantion of DHA 2 a and 2-ethylanthracener8=Iwhich proceeds by H transfer, and the gasphase reaction of ethylene and cyclopentene which occurs at
400-500 oC[8b1
are exceptions.
We report here on experiments that prove that the hydrogenation of cc-methylstyrene(I) by DHA 2a is one of the few
examples of a stoichiometric, solution-phase, uncatalyzed
transfer hydrogenation of an alkene initiated by the bimolecular formation of a radical by H transfer from a C-H bond.
Thus this reaction is a suitable subject for a mechanistic
study of the type of ''molecule-induced"[91radical formation
discussed as the initiation step in the uncatalyzed polymerization of styrene.
Kinetic measurements (Table 1) show that the rate of the
H-transfer reaction [Eq. (l)] is first order in DHA 2a and in
a-methylstyrene (1) up to high conversions. Both the decrease in the concentration of 1 ( k , ) and the increase of the
concentration of 3 (k;)were followed by gas chromatography and provided the same results.
The rate constant of the bimolecular reaction is almost
independent of the concentration of the H donor, invariant
to oxygen, and also unchanged upon addition of the initiator
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acid, chiral, complexation, spirobifluoren, functionalized, enantioselectivity, cleft, dicarboxylic
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