Synthesis and fluorescence properties of manisyl-substituted terpyridine, bipyridine, and phenanthroline

Article abstract of DOI:10.1002/1521-3773(20010216)40:4<754::AID-ANIE7540>3.0.CO;2-T

As a hybrid of two aryl motifs, that is p-anisyl and mesityl, the 4-methoxy-2,6-dimethylphenyl or "manisyl" substituent offers possibilities for further structural elaboration as well as enhancing the solubility of the heterocyclic ligands mentioned in th

Full text of DOI:10.1002/1521-3773(20010216)40:4<754::AID-ANIE7540>3.0.CO;2-T

COMMUNICATIONS
graphic data (excluding structure factors) for the structure reported in
this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC-148212. Copies
of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033;
e-mail: deposit@ccdc.cam.ac.uk).
In conclusion, the concept of an accessible and controllable
molecular program, even within the limited arena of metal
coordination structures, seems premature. If one wants to
ªprogramº in the ªmachine languageº of molecules, (s)he will
receive the greatest insight from the firm fundamentals of
thermodynamics and kinetics as opposed to distractions of
sirenous supramolecular slogans.
[24] F. Cozzi, M. Cinquini, R. Annunziata, T. Dwyer, J. S. Siegel, J. Am.
Chem. Soc. 1992, 114, 5729.
[25] F. Cozzi, M. Cinquini, R. Annuziata, J. S. Siegel, J. Am. Chem. Soc.
1993, 115, 5330.
Received: August 16, 2000 [Z15648]
[26] F. Cozzi, J. S. Siegel, Pure Appl. Chem. 1995, 67, 683.
[27] F. Cozzi, F. Ponzini, R. Annunziata, M. Cinquini, J. S. Siegel, Angew.
Chem. 1995, 107, 1092; Angew. Chem. Int. Ed. Engl. 1995, 34, 1019.
[28] W. L. Jorgensen, D. L. Severance, J. Am. Chem. Soc. 1990, 112, 4768.
[29] C. A. Hunter, J. K. M. Sanders, J. Am. Chem. Soc. 1990, 112, 5525.
[30] C. A. Hunter, Angew. Chem. 1993, 105, 1653; Angew. Chem. Int. Ed.
Engl. 1993, 32, 1584.
[1] J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspectives,
VCH, Weinheim, 1995.
[2] D. M. Bassani, J.-M. Lehn, K. Fromm, D. Fenske, Angew. Chem. 1998,
110, 2534; Angew. Chem. Int. Ed. 1998, 37, 2364.
[3] P. N. W. Baxter, J.-M. Lehn, B. O. Kneisel, D. Fenske, Angew. Chem.
1997, 109, 2067; Angew. Chem. Int. Ed. 1997, 36, 1978.
[4] D. Venkataraman, Y. Du, S. R. Wilson, K. A. Hirsch, P. Zhang, J. S.
Moore, J. Chem. Educ. 1997, 74, 915.
[31] C. A. Hunter, Chem. Soc. Rev. 1994, 23, 101.
[32] J. Bernstein, M. C. Etter, L. Leiserowitz in Structure Correlation,
Vol. 2 (Eds.: H.-B. Bürgi, J. D. Dunitz), VCH, Weinheim, 1994,
pp. 431 ± 507.
[5] M. Fujita, Acc. Chem. Res. 1999, 32, 53.
[33] A. Gavezzotti in Structure Correlation, Vol. 2 (Eds.: H.-B. Bürgi, J. D.
Dunitz), VCH, Weinheim, 1994, pp. 509 ± 542.
[34] J. D. Dunitz, A. Gavezzotti, Acc. Chem. Res. 1999, 32, 677.
[35] J. Sandström, Dynamic NMR Spectroscopy, Academic Press, New
York, 1982.
[6] M. Fujita in Comprehensive Supramolecular Chemistry, Vol. 9 (Eds.:
J. L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle, J.-M. Lehn),
Pergamon, Oxford, 1996, pp. 253 ± 280.
[7] D. L. Caulder, K. N. Raymond, Acc. Chem. Res. 1999, 32, 975.
[8] S. Leininger, B. Olenyuk, P. J. Stang, Chem. Rev. 2000, 100, 853.
[9] P. J. Stang, B. Olenyuk, Acc. Chem. Res. 1997, 30, 502.
[10] P. J. Stang, Chem. Eur. J. 1998, 4, 19.
[11] P. N. W. Baxter, J.-M. Lehn, J. Fischer, M.-T. Youinou, Angew. Chem.
1994, 106, 2432; Angew. Chem. Int. Ed. Engl. 1994, 33, 2284.
[12] G. S. Hanan, D. Volkmer, U. S. Schubert, J.-M. Lehn, G. Baum, D.
Fenske, Angew. Chem. 1997, 109, 1929; Angew. Chem. Int. Ed. Engl.
1997, 36, 1842.
[13] J. Rojo, J.-M. Lehn, G. Baum, D. Fenske, O. Waldmann, P. Müller, Eur.
J. Inorg. Chem. 1999, 517.
[14] P. N. W. Baxter, J.-M. Lehn, B. O. Kneisel, D. Fenske, Chem.
Commun. 1997, 2231.
Synthesis and Fluorescence Properties of
Manisyl-Substituted Terpyridine, Bipyridine,
and Phenanthroline**
Jon C. Loren and Jay S. Siegel*
[15] J.-M. Lehn, Angew. Chem. 1990, 102, 1347; Angew. Chem. Int. Ed.
Engl. 1990, 29, 1304.
[16] D. P. Funeriu, J.-M. Lehn, G. Baum, D. Fenske, Chem. Eur. J. 1997, 3,
99.
[17] P. G. Sammes, G. Yahioglu, Chem. Soc. Rev. 1994, 23, 327.
[18] E. C. Constable in Comprehensive Supramolecular Chemistry, Vol. 9
(Eds.: J. L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle, J.-M.
Lehn), Pergamon, Oxford, 1996, pp. 213 ± 252.
[19] C. O. Dietrich-Buchecker, J.-P. Sauvage in Bioorganic Chemistry
Frontiers, Vol. 2 (Ed.: H. Dugas), Springer, Berlin, 1991, pp. 195 ± 248.
[20] R. F. Carina, C. Dietrich-Buchecker, J.-P. Sauvage, J. Am. Chem. Soc.
1996, 118, 9110.
[21] S. Toyota, C. R. Woods, M. Benaglia, J. S. Siegel, Tetrahedron Lett.
1998, 39, 2697.
Cation affinity, solubility, and spectroscopy (e.g. fluores-
cence) are three characteristic physical properties of oligo-
pyridine-based heterocycles (2,2':6',2''-terpyridines, 2,2'-bipyr-
idines, and 1,10-phenanthrolines, in the following simply
designated as terpyridines, bipyridines, and 1,10-phenanthro-
lines) that one would like to control through a simple
synthesis scheme from common building blocks.[1] In partic-
ular, aryl-substituted heterocycles of this family have a rich
history in metal coordination chemistry.[2, 3] Their conjugated
backbones make them attractive chromophores and molec-
ular ªantennaeº;[4±7] however, the larger and fused analogues
typically suffer from poor solubility and inefficient chemical
syntheses. Among aryl substituents, p-anisyl (4-methoxyphen-
yl) has been extensively used where further structural
elaboration was desired,[8±10] and mesityl has been noted for
endowing superior solubility features.
[22] J. Nasielski, A. Standaert, R. Nasielski-Hinkens, Synth. Commun.
1991, 21, 901.
[23] Crystal structure analysis: Bruker P4 four-circle diffractometer,
rotating-anode generator, Hi-Star area detector, CuKa radiation (l ˆ
1.54178 Š), graphite monochromator, W scans, Tˆ 295(2) K, cell
determination with 3053 reflections (18 < q < 458), data collection,
data reduction, Lorentz and polarization corrections carried out using
FRAMBO and SAINT. Structure solution by direct methods,
remaining non-H atoms by LS DF syntheses, refinement against
F 2 (SHELXH) with all H atoms included in idealized positions, BF4
ions disordered so B F distances were restrained to be approximately
1.43 Š, all non-H atoms refined anisotropically except atoms in
pendant anisole groups which were kept isotropic. Structure solution,
refinements, graphics, and tables calculations performed with
SHELXTL/PC. 1. C228H156B4Cu4F16N24O12, Mr ˆ 4025.17, monoclinic,
space group P21/n (no. 14), a ˆ 17.5893(1), b ˆ 40.3378(9), c ˆ
A hybrid of these two aryl motifs, 4-methoxy-2,6-dimethyl-
phenyl or ªmanisylº, offers both characteristics, but has been
[*] Prof. J. S. Siegel, J. C. Loren
Department of Chemistry, University of California, San Diego
La Jolla, CA 92093-0358 (USA)
Fax : (‡1)858-822-0386
E-mail: jss@chem.ucsd.edu
30.5005(4) Š, b ˆ 94.590(1)8, Vˆ 21571.1(6) Š3, Z ˆ 4, 1calcd
ˆ
1.239 gcm 3, m(CuKa) ˆ 1.083 mm 1, crystal dimensions ca. 0.063 Â
0.030  0.030 mm3, 2qmax ˆ 90.648, 31168 reflections measured, 12441
unique reflections (Rint ˆ 0.197), 1756 parameters, 23 restraints,
R1(wR2) ˆ 0.1524(0.2278) for 6194 reflections with I > 2s(I). Crystallo-
[**] Manisyl ˆ 4-methoxy-2,6-dimethylphenyl. This work was supported
by the US National Science Foundation (CHE-9904275).
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
754
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4004-0754 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 4

COMMUNICATIONS
virtually absent as a substituent in this family of heterocyclic
compounds. Here we present a general route to these aryl-
substituted heterocycles using palladium-mediated coupling
of organozinc halides with heterocyclic halides, and note an
extraordinary suitability of zinc to complex with the in situ
forming ligand, thus protecting the catalyst from poisoning
and simplifying product purification. A further highlight of
this work stems from the ability of the manisyl group to endow
specific members of this family with high fluorescence
quantum efficiency. Therefore, in one concentrated effort
we have been able to address problems related to the
chemical synthesis, physical manipulation, and photophysical
properties of these versatile metal chelates.
Considering substitution at the a, b, and g positions relative
to the nitrogen atom of a pyridine and including the
combinations of pyridine and phenanthroline up to tridentate
chelates (pyridine, bipyridine, terpyridine, phenanthroline,
and pyridylphenanthroline) generates a family of 42 struc-
tures, from which a representative subset of 17 were targeted
for synthesis, with manisyl as the prototypical substituted
arene. An appropriate set of halogenated pyridines (1a ± e)
and phenanthrolines (2a ± d) were available either commer-
cially or from literature procedures.[11±15] Starting from
commercially available 3,5-dimethylanisole, the literature-
known 4-methoxy-2,6-dimethylbromobenzene (3-Br) was
prepared[16] and then converted into the organozinc reagent
3-ZnCl by employing Negishi conditions.[17±19] Halopyridines
1a ± c and 1e react smoothly with one molar equivalent of 3-
ZnCl to form the corresponding arylpyridines, of which 4-Br,
5-Br, and 6-I can be converted to the organozinc analogue.[20]
These six sets of building blocks can be permuted between
organozinc and halide counterparts in a series of Negishi
couplings to generate a large array of ligand patterns
(Scheme 1). For example, symmetrical terpyridines (12 ± 14)
were prepared from two molar equivalents of an organozinc
and 1b in about 60% yield (Table 1).
Table 1. Substrates and yields for the synthesis of heterocycles 7 ± 21.
Aryl ± ZnCl
Aryl ± X
Product
Yield [%][a]
Melting range [8C][b]
3-ZnCl
3-ZnCl
3-ZnCl
3-ZnCl
3-ZnCl
3-ZnCl
3-ZnCl
3-ZnCl
4-ZnCl
5-ZnCl
6-ZnCl
4-ZnCl
5-ZnCl
5-ZnCl
5-ZnCl
6-ZnCl
5-ZnCl
3-ZnCl
1b
1c
1e
1a
2c
4-Br
5-Br
6-H
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
61
85
98
75
70
69
15
67
50
62
11
59
31
59
59
21
77
81
75 ± 77
78 ± 80
98 ± 100
53 ± 54
248 ± 249
234 ± 235
255 (decomp)
244 ± 245
215 ± 216
224 ± 225
272 ± 274
231 ± 233
164 ± 166
257 ± 258
94 ± 96
2a
2d
2b
1b
1b
1b
4-Br
4-Br
5-Br
1d
6-I
2b
20
272 ± 274
112 ± 118
130 ± 134
[a] Yields based on isolated product after purification. [b] Melting points
are uncorrected.
Scheme 1. a) n-Butyllithium, 788C, THF; ZnCl2, THF, 788C !RT; b) Aryl ± X, 5% [Pd(PPh3)4], reflux, 12 h, THF; c) see ref. [20].
Angew. Chem. Int. Ed. 2001, 40, No. 4 ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 1433-7851/01/4004-0755 $ 17.50+.50/0
755

COMMUNICATIONS
A special highlight of the method was the ease with which
the peculiar pyridylphenanthroline 21 was prepared as a
highly soluble terpyridine analogue.[21] In some cases the zinc
complex of the ligand precipitates at the end of the reaction.
This solid can be readily separated from the organic by-
products after which the zinc cation can be removed by an
EDTA extraction to leave the pure ligand. In addition,
all compounds prepared could be isolated in pure form
by column chromatography on alumina with hexanes/di-
chloromethane. The transferability of reaction conditions
across this series of derivatives indicates that this method is
generally applicable to the synthesis of any aryl/alkyl cognate
that will tolerate the formation/presence of organozinc
halides.[22, 23]
Figure 1. Bar graph of fluorescence quantum yield for heterocycles 7 ± 21.
Table 2. Excitation and emission wavelengths of free ligands (L), selected
‡
protonated ligands (L-H ),[a] zinc-bound ligands (L-Zn2‡),[b] and fluores-
The solubility of all manisyl derivatives in organic solvents
is superior to that of the simple phenyl- or anisyl-substituted
heterocycles (e.g., the solubility of dimanisyl terpyridine 13
compared to that of its anisyl cognate in chloroform, dichloro-
methane, tetrahydrofuran and acetone are 230, 210, 95, and
cence quantum yields (Ff)[c] recorded in CH3CN.
‡
‡
L
L
Ff
L-H
L-H
L-Zn2‡
L-Zn2‡
lex [nm] lem [nm]
lex [nm] lem [nm] lex [nm] lem [nm]
7
8
9
285
270
266
358
405
380
412
383
412
408
417
408
409
408
410
414
443
0.05
0.27 356
0.02
0.06
0.04
0.08
0.85 368
0.05
1
1
10 mgmL versus 2, >1, >1, >1 mgmL , respectively).
Facile deprotection of the methoxy group by pyridinium
hydrochloride has been demonstrated for terpyridine 13, and
the resulting phenolic derivative remains soluble. Realkyla-
tion of the phenolic oxygens occurred by standard methods
(e.g. allyl bromide in the presence of potassium carbonate in
acetonitrile) without problems, which makes it clear that these
ligands will be directly applicable to the synthesis of larger
supramolecular coordination complexes and will be instru-
mental in the elaboration of new topological stereoisom-
ers[9, 24] and materials incorporating metal binding sites.[25]
Presumably the solubility of the manisyl derivatives stems
from the orthogonal conformation at the aryl ± pyridyl bond
due to the proximal methyl groups. This conformation should
also prohibit the effectiveness of normal planar conjugation.
Curiously, terpyridine 13 displays a very bright fluorescence
(lem 408 nm; lmax 286 nm) with a quantum yield (Ff) of 0.85 in
acetonitrile and retains fluorescence in water.[26, 27] The
possibility of a type of spiroconjugation or twisted excited
state electron transfer thus arises.[27, 28] The ease of the
synthetic method provided access to a large swath of
structural space and the ability to probe structural depen-
dence of this fluorescence behavior. Classifying the quantum
yields for the 17 representative ligands as high (Ff > 0.75),
medium (0.25 < Ff < 0.75), and low (Ff < 0.25), one immedi-
ately sees that manisyl substitution b to the nitrogen atom is a
common structural feature of the high quantum yield group,
13, 17, and 18 (Figure 1).[29] The control comparison of
pyridine 7 with bipyridine 18 shows low and high efficiency,
respectively, and establishes the principal ªminimumº chro-
mophore. The compounds of medium quantum yield (8, 16,
and 21) also bear a manisyl group in the b position.
Substitution only a or only g resulted in quantum yields
significantly lower than 20%, with the g set slightly more
efficient than the a set. Protonation of the heterocycle results
in a standard red shift of about 30 ± 100 nm in the absorption
spectrum and emission maxima. The presence of zinc as a
complexing metal causes a shift in the spectra of the ligands in
the high- and medium-efficiency group (Table 2). Protonation
and metalation display clean isosbestic behavior. A full
449
535
322
340
486
512
10 267
11 270
12 284
13 286
14 279
15 282
16 290
17 296
18 286
19 282
21 296
0.02
0.48 350
0.87 350
0.78 310
0.15
532
569
499
314
320
308
516
491
496
0.44 368
541
366
537
[a] Excess CH3SO3H. [b] Excess ZnCl2. [c] Measured relative to 9,10-
diphenylanthracene.
analysis of the fluorescence behavior as a function of aryl
substitution is underway.
In conclusion, a simple general procedure for the synthesis
of a-, b-, and g-substituted bipyridines, terpyridines, phenan-
throlines, and pyridylphenanthrolines has been developed on
the basis of palladium-mediated coupling of organozinc
halides and halogenated heterocycles. The method has been
showcased with the ªmanisylº (4-methoxyl-2,6-dimethylphen-
yl) group as the aryl prototype. The manisyl group adds
desirable functionality that results in facile chemical elabo-
ration, superior solubility and high fluorescence quantum
yield. The compounds prepared here are representative of a
much larger class of imaginable aryl-substituted heterocycles
that will be important ligands for metal chelation, supra-
molecular complexation, topological isomer construction and
fluorophore generation.[30, 31] Such auspicious spectral and
complexation features point to the use of such compounds in
recognition,[32] sensor,[32] tagging,[33] and catalytic applica-
tions.[34]
Experimental Section
21:[35] To a solution of 3-Br (0.206 g, 0.957 mmol) in THF (20 mL) at 788C
was added nBuLi (0.60 mL of a 1.6m solution in hexane, 0.96 mmol). To this
mixture was added a 08C solution of zinc chloride (0.130 g, 0.96 mmol) in
THF (5 mL) by cannula and allowed to warm to room temperature.
756
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4004-0756 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 4

COMMUNICATIONS
Subsequently, a solution of 20 (0.300 g, 0.638 mmol) and [Pd(PPh3)4]
(0.055 g, 0.048 mmol) in THF (5 mL) was added to the organozinc
intermediate by cannula. The mixture was heated at reflux for 20 h, cooled
to room temperature, and placed in a freezer. The white precipitate was
filtered, washed with cold THF, and dried. The precipitate was dissolved in
dichloromethane and extracted vigorously with saturated aqueous EDTA
and basified with saturated aqueous sodium bicarbonate. The organic layer
was separated, dried over magnesium sulfate, filtered, and evaporated to
afford a white crystalline solid (270 mg, 81%), m.p. 130 ± 1348C. 1H NMR
(300 MHz, CDCl3): d ˆ 9.05 (d, J ˆ 2.0 Hz, 1H), 9.04 (d, J ˆ 8.0 Hz, 1H),
8.83 (d, J ˆ 8.5 Hz, 1H), 8.53 (d, J ˆ 2.0 Hz, 1H), 8.41 (d, J ˆ 8.5 Hz, 1H),
8.06 (d, J ˆ 2.0 Hz, 1H), 7.88 (d, J ˆ 9.0 Hz, 1H), 7.81 (d, J ˆ 9.0 Hz, 1H),
7.72 (dd, J ˆ 2.0, 8.0 Hz, 1H), 6.74 (s, 2H), 6.70 (s, 2H), 3.84 (s, 3H), 3.82 (s,
3H), 2.07 (s, 6H), 2.05 (s, 6H); 13C NMR (100 MHz, CDCl3): d ˆ 158.85,
158.67, 156.12, 154.37, 151.80, 149.63, 145.51, 144.67, 138.38, 137.83, 137.67,
136.89, 136.41, 135.84, 130.23, 130.01, 128.66, 128.49, 126.62, 122.41, 120.56,
112.88, 112.82, 55.23, 55.20, 21.43, 21.34; UV/Vis (CH3CN): lmax (e) ˆ 240
(6.3 Â 104), 296 (4.3 Â 104), 354 (8.7 Â 103) nm; HR-MS: m/z: calcd for
C35H31N3O2: 525.2416; found: 525.2407.
[22] S. A. Savage, A. P. Smith, C. L. Fraser, J. Org. Chem. 1998, 63, 10048.
[23] S. L. Hargreaves, B. L. Pilkington, S. E. Russell, P. A. Worthington,
Tetrahedron Lett. 2000, 41, 1653.
[24] D. M. Walba, Tetrahedron 1985, 41, 3161.
[25] J.-M. Lehn, Makromol. Chem. Macromol. Symp. 1993, 69, 1.
[26] J. N. Demas, G. A. Crosby, J. Phys. Chem. 1971, 75, 991.
[27] J. R. Lakowicz, Principles of Fluorescence Spectroscopy, Kluwer, New
York, 1999.
[28] W. Rettig, Top. Curr. Chem. 1994, 169, 1.
[29] In a related set of 3,8-bis(phenethynyl)phenanthrolines, Tor and co-
workers have seen high fluorescence quantum yields and emission
tunability, see H. S. Joshi, R. Jamshidi, Y. Tor, Angew. Chem. 1999,
111, 2888; Angew. Chem. Int. Ed. 1999, 38, 2722.
[30] V. Balzani, A. Credi, M. Venturi, Coord. Chem. Rev. 1998, 171, 3.
[31] P. Belser, S. Bernhard, C. Blum, A. Beyeler, L. De Cola, V. Balzani,
Coord. Chem. Rev. 1999, 192, 155.
[32] Chemosensors of Ion and Molecular Recognition (Eds.: J.-P. Des-
vergnes, A. Czarnik), Kluwer, Dordrecht, 1997, 245 (492, N. ASI).
[33] V. M. Mukkala, M. Helenius, I. Hemmila, J. Kankare, H. Takalo, Helv.
Chim. Acta 1993, 76, 1361.
Received: August 28, 2000 [Z15713]
[34] J. Seyden-Penne, Chiral Auxiliaries and Ligands in Asymmetric
Synthesis, Wiley, New York, 1995.
[35] Although written explicitly for the novel heterocycle 21, this
exemplifies a general procedure for any of the compounds reported.
[1] U. S. Schubert, C. Eschbaumer, Org. Lett. 1999, 1, 1027; O. Henze, U.
Lehmann, A. D. Schlüter, Synthesis 1999, 683; U. Lehmann, O. Henze,
A. D. Schlüter, Chem. Eur. J. 1999, 5, 854; J.-P. Sauvage, M. Ward,
Inorg. Chem. 1991, 30, 3869; and the classic work of F. Kröhnke,
Synthesis 1976, 1.
[2] A. von Zelewsky, Stereochemistry of Coordination Compounds, Wiley,
Chichester, 1996.
[3] E. C. Constable in Comprehensive Supramolecular Chemistry, Vol. 9
(Eds.: J. L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle, J.-M.
Lehn), Pergamon, Oxford, 1996, p. 165.
[4] T. Yamamoto, Y. Yoneda, K. Kizu, Macromol. Rapid Commun. 1995,
16, 549.
[5] B. Alpha, R. Ballardini, V. Balzani, J.-M. Lehn, S. Perathoner, N.
Sabbatini, Photochem. Photobiol. 1990, 52, 299.
[6] B. Alpha, V. Balzani, J.-M. Lehn, S. Perathoner, N. Sabbatini, Angew.
Chem. 1987, 99, 1310; Angew. Chem. Int. Ed. Engl. 1987, 26, 1266.
[7] B. Alpha, J.-M. Lehn, G. Mathis, Angew. Chem. 1987, 99, 259; Angew.
Chem. Int. Ed. Engl. 1987, 26, 266.
[8] C. Dietrich-Buchecker, J.-P. Sauvage, New J. Chem. 1992, 16, 277.
[9] J.-P. Sauvage, Acc. Chem. Res. 1990, 23, 319.
[10] J.-P. Sauvage, Acc. Chem. Res. 1998, 31, 611.
[11] Pyridine 1c was prepared by lithiation of commercially available 2,5-
dibromopyridine and quenching with elemental iodine.
[12] M. Schmittel, A. Ganz, Synlett 1997, 710.
[13] M. Levis, U. Lüning, M. Müller, M. Schmittel, C. Wöhrle, Z.
Naturforsch. B 1994, 49, 675.
Parallel Reactions for Enantiomeric
Quantification of Peptides by Mass
Spectrometry**
W. Andy Tao and R. Graham Cooks*
The accelerating trend towards the use of enantiomerically
pure compounds as drugs has underscored the need for new
methods of enantioselective synthesis and chiral analysis.[1]
The capabilities of mass spectrometry for the rapid analysis of
complex mixtures have encouraged its exploration for gas-
phase chiral recognition.[2] This has been achieved by direct
measurement of the relative abundance of two diastereomeric
ions formed by complexing enantiomers and a chiral refer-
ence,[2d,g±i] ion ± molecule reactions of diastereomeric ad-
ducts,[2c,e] or collisional dissociation of diastereomers.[2b]
Quantitative analysis, especially when one enantiomer com-
prises only a few percent of a mixture, remains a challenge.
Competitive reactions of two enantiomers toward a chiral
reference are unavoidably influenced by the relative concen-
trations of the enantiomers, which affects the accuracy of the
measurement of the enantiomeric excess (ee) unless the
selectivity factor s (the ratio of competing rate constants) is
[14] S. Toyota, C. R. Woods, M. Benaglia, J. S. Siegel, Tetrahedron Lett.
1998, 39, 2697.
[15] D. Tzalis, Y. Tor, S. Failla, J. S. Siegel, Tetrahedron Lett. 1995, 36, 3489.
[16] A. Pelter, R. Drake, Tetrahedron 1994, 50, 13775.
[17] I. Klement, M. Rottlander, C. E. Tucker, T. N. Majid, P. Knochel, P.
Venegas, G. Cahiez, Tetrahedron 1996, 52, 7201.
[18] E. Negishi, J. Org. Chem. 1977, 42, 1821.
[19] E. Negishi, T. Takahashi, A. O. King, Org. Synth. 1988, 66, 67.
[20] Because of the instability of 4-halopyridines, the hydrochloride of 1e
was used in combination with 2 molar equivalents of 3-ZnCl under
otherwise analogous Negishi conditions to produce 6-H. This inter-
mediate is treated with sodium amide in dimethyl aniline (Chichibabin
conditions) to produce the 2-aminopyridine, see: J.-C. Chambron, J.-P.
Sauvage, Tetrahedron 1987, 43, 895. The 2-aminopyridine is converted
to 6-I by reaction with isoamylnitrite and iodine in toluene (non-
aqueous Sandmeyer conditions), see: L. Friedman, J. F. Chlebowski, J.
Org. Chem. 1968, 33, 1636.
[*] Prof. R. G. Cooks, W. A. Tao
Department of Chemistry
Purdue University
West Lafayette, IN 47907 (USA)
Fax : (‡1)765-494-9421
E-mail: cooks@purdue.edu
[21] For recent reports of the parent heterocycle and an alkyl/aryl
derivative see: C. Y. Hung, T. L. Wang, Z. Q. Shi, R. P. Thummel,
Tetrahedron 1994, 50, 10685; J.-P. Collin, P. Gavina, J.-P. Sauvage, A.
DeCian, J. Fischer, Aust. J. Chem. 1997, 50, 951, respectively; see also:
[**] This work was supported by the U.S. Department of Energy, Office of
Energy Research. W.A.T. acknowledges fellowship support from
Triangle Pharmaceuticals.
Ä
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
F. Barigelletti, B. Ventura, J.-P. Collin, R. Kayhanian, P. Gavina, J.-P.
Sauvage, Eur. J. Inorg. Chem. 2000, 113 ± 119.
Angew. Chem. Int. Ed. 2001, 40, No. 4
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4004-0757 $ 17.50+.50/0
757