Efficient synthesis and structural characteristics of zwitterionic twisted π-electron system biaryls

Article abstract of DOI:10.1021/ol051365x

(Chemical Equation Presented) A series of unconventional twisted π-electron system molecules has been synthesized via Suzuki cross-coupling of two sterically hindered arenes. Crystallographic analysis of these molecules reveals a large ring-ring dihedral

Full text of DOI:10.1021/ol051365x

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3721-3724
Efficient Synthesis and Structural
Characteristics of Zwitterionic Twisted
π
-Electron System Biaryls
Hu Kang,† Antonio Facchetti,† Charlotte L. Stern,† Arnold L. Rheingold,‡
W. Scott Kassel,‡ and Tobin J. Marks*,†
Department of Chemistry and the Materials Research Center, Northwestern UniVersity,
EVanston, Illinois 60208-3113, and Department of Chemistry and Biochemistry,
UniVersity of California, San Diego, La Jolla, California 92093-0332
t-marks@northwestern.edu
Received June 10, 2005
ABSTRACT
A series of unconventional twisted
arenes. Crystallographic analysis of these molecules reveals a large ring
ground state. An efficient conversion of phenols into aryl halides is also reported.
π
-electron system molecules has been synthesized via Suzuki cross-coupling of two sterically hindered
−
ring dihedral twist angle (87 ) and a highly charge-separated zwitterionic
°
Organic chromophores exhibiting very large hyperpolariz-
abilities have attracted considerable current research interest
due to their potential applications in novel photonic tech-
nologies such as high-speed optical communications, optical
data processing and storage, and integrated optics.1 To date,
most of the organic molecules developed for this purpose
consist of extended planar π-conjugated systems end-capped
with electron donor and acceptor substituents,2 which are
inherently elaborate structurally, complicating synthetic
approaches, and frequently subject to chemical, thermal, and
photochemical instability.3 Recent computational investiga-
tions4 indicate that relatively simple zwitterionic molecules
with twisted π-electron systems, TICTOID (twisted intramo-
lecular charge transfer) structures (Figure 1), should exhibit
very large hyperpolarizabilities and two-photon absorption
† Northwestern University.
‡ University of California, San Diego.
(1) (a) Dalton, L. AdV. Polym. Sci. 2002, 158, 1. (b) Kuzyk, M. G. Phys.
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(Special Issue: Molecular Nonlinear Optics: Materials, Phenomena and
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Persoons, A. J. Mater. Chem. 1997, 7, 2175. (e) Marder, S. R.; Kippelen,
B.; Jen, A. K. Y.; Peyghambarian, N. Nature 1997, 388, 845. (f) Marks, T.
J.; Ratner, M. A. Angew. Chem., Int. Ed. Engl. 1995, 34, 155.
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Figure 1. Twisted π-electron system chromophores.
cross-sections. The exceptional responses arise from the very
strong sensitivity of the charge separation and excited-state
(3) Galvan-Gonzalez, A.; Belfield, K. D.; Stegeman, G. I.; Canva, M.;
Marder, S. R.; Staub, K.; Levina, G.; Twieg, R. J. J. Appl. Phys. 2003, 94,
756 and references therein.
10.1021/ol051365x CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/28/2005

charge redistribution to the inter-ring twist angle, which is
tuned by introducing sterically encumbered R1 and R2
substituents. Notably, the mechanism of the response to the
light field is distinctly different from the current models such
as “bond length alternation”5 and “auxiliary donor and
acceptor”.6 Synthetic access to such chromophores could
therefore have a major impact on organic electro-optics.
The synthetic challenge posed by this type of chromophore
is obvious: formation of highly hindered substitution patterns
via the coupling of two arenes possessing bulky ortho
substituents. In this contribution, we report the synthetic
realization of the first twisted π-electron system molecules
(TMs; Figure 1),7 merocyanine-based dyes containing a tetra-
ortho-methylbiaryl core, and their molecular structural
characteristics.
Among the catalytic cross-coupling reactions for unsym-
metrical biaryl synthesis, limited success has been realized
with Stille and Negishi protocols when coupling sterically
hindered fragments,8 while the Suzuki method has shown
more tolerance to steric effects.9,10 Recently, Buchwald et
al. reported a highly active Pd(0)/phenanthrene-based phos-
phine Suzuki catalyst for the synthesis of tetra-ortho-
substituted biaryls, with substituents such as methyl, primary
alkyl, phenyl, and alkoxyl groups accommodated.10a In the
case of electron-deficient heteroarenes, however, our initial
attempts to couple 3,5-dimethyl-4-bromopyridine with 4-meth-
oxyl-2,6-dimethyl phenylboronic acid (2, Scheme 1) employ-
conditions. Usually, electron-deficient pyridine halides are
reactive with respect to oxidative addition processes, often
turnover-limiting in the Suzuki catalytic cycle.11 The slug-
gishness of the present coupling reaction implies that
reductive elimination may be turnover-limiting, presumably
due to slow formation of a requisite but sterically encumbered
cis-Pd(II)(aryl)2 intermediate. Such sluggishness in Suzuki
coupling was also observed in hindered aryl halides pos-
sessing ortho electron-withdrawing groups using the same
catalyst.10a An alternative reason for this inertness in
catalyzed coupling may be inhibition by pyridine,12 displac-
ing a phosphine ligand to form unproductive complexes in
some Pd-catalyzed aminations.12 To investigate this pos-
sibility, 4-bromopyridine N-oxide 1 was used as a coupling
partner with boronic acid 2, successfully affording the key
tetra-ortho-methylphenylpyridine core 3 in 53% yield (Scheme
1). Interestingly, the N-oxide functionality does not appear
to induce detrimental oxidation of the Pd(0) form of the
catalyst. Pyridine N-oxide 3 was next reduced to 4 using
Pd-catalyzed hydrogenation with sodium hypophosphite as
the hydrogen source.13 This deoxygenation is facile and
quantitative. Subsequent cleavage of the 4 methoxyl group
affords pyridylphenol intermediate 5 in high yield, which
was then quaternized with methyl iodide and deprotonated
to afford chromophore TM-1 almost quantitatively.
The synthetic approach to chromophore TM-2 relies on
Heck cross-coupling (Scheme 2), known to be efficient in
Scheme 2. Synthesis of Twisted π-System Molecule TM-2
Scheme 1. Synthesis of Twisted π-System Molecule TM-1
forming C-C connections between sp2 carbons and to be
highly stereoselective for the (E)-stereoisomer.14 Styrenic
coupling partner 7 was obtained from the thermal decar-
(8) (a) Saa´, J. M.; Martorell, G. J. Org. Chem. 1993, 58, 1963. (b) Dai,
C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.
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ing this catalyst system were unsuccessful in affording the
key tetra-ortho-methylbiaryl core under standard reaction
(4) (a) Keinan, S.; Zojer, E.; Bredas, J.-L.; Ratner, M. A.; Marks, T. J.
THEOCHEM 2003, 633 (2-3), 227. (b) Pati, S. K.; Marks, T. J.; Ratner,
M. A. J. Am. Chem. Soc. 2001, 123, 7287. (c) Albert, I. D. L.; Marks, T.
J.; Ratner, M. A. J. Am. Chem. Soc. 1998, 120, 11174.
(5) Marder, S. R.; Cheng, L. T.; Tiemann, B. G.; Friedli, A. C.;
Blanchard-Desce, M.; Perry, J. W.; Skindhoej, J. Science 1994, 263, 511.
(6) Albert, I. D. L.; Marks, T. J.; Ratner, M. A. J. Am. Chem. Soc. 1997,
119, 6575.
(7) DFT/ZINDO computations predict hyperpolarizability (â0) as -123
× 10-30 and -2552 × 10-30 esu for TM-1 and TM-2, respectively (Keinan,
S.; Ratner, M. A. Unpublished results).
(11) (a) Lohse, O.; Thevenin, P.; Waldvogel, E. Synlett 1999, 1, 45. (b)
Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(12) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240.
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Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379.
3722
Org. Lett., Vol. 7, No. 17, 2005

boxylation of 3,5-di-tert-butyl-4-hydroxycinnamic acid in
DMF.15 When the conventional Heck Pd(OAc)2/PPh3 catalyst
system is employed, 7 undergoes coupling with various
twisted triflate (6a), bromide (6b), and iodide (6c) substrates
to afford the stilbene precursor 8 in moderate to excellent
yields of 50, 54, and 91%, respectively. Precursor 8 was then
quaternized with n-octyl iodide and deprotonated to afford
TM-2.
Scheme 3. Conversion of Phenol Intermediate 5 to Aryl
Halides 6b and 6c
Halide precursors 6b and 6c are important not only for
facilitating the Heck coupling but also for facilitating
introduction of stronger, more stable electron donor func-
tionalities such as the dicyanomethanide group,16 which could
not be introduced by triflate nucleophilic substitution at 6a.17
Converting phenol 5 into aryl halides, which can undergo
cross-coupling with active methylene compounds such as
malononitrile in the presence of Pd catalysts,18 is thereby
highly desirable. Few methods have been reported for direct
conversion of phenols to aryl halides.19 Attempts to synthe-
size 6b via thermolysis of the phenol-triphenylphosphine
dibromide complex19a were unsuccessful. The displacement
of triflate by iodide or bromide is usually feasible in activated
aryl triflates possessing ortho or para electron-withdrawing
groups20 but in the present case was unsuccessful in affording
bromide 6b and iodide 6c. We therefore devised a new
strategy to convert the phenol 5 to bromide 6b and iodide
6c by combining Pd-catalyzed aryl triflate amination21 with
the arylamine-to-aryl halide conversion (Scheme 3). The
conversion began with Pd-catalyzed coupling of triflate 6a
with benzophenone imine, leading to diphenyl ketimine
adduct 9 in 98% yield. Subsequent quantitative hydrolysis
of 9 to the primary aniline 10 was facilitated by hydroxy-
lamine hydrochloride. Next, aniline 10 was converted into
the corresponding halides via anhydrous Sandmeyer-like
reactions,22 since conventional Sandmeyer methods in aque-
ous media23 gave only low yields and complicated products.
Aniline 10 was treated with tert-butyl nitrite and anhydrous
CuBr2 in dry CH3CN to produce bromide 6b rapidly,
accompanied by the formation of di- and tribrominated
byproducts due to competitive oxidative CuBr2 bromina-
tion.22a,24 The multibrominated byproducts, even in low
yields, complicate purification and result in moderate yields
of the desired monobrominated product (50%) after multiple
recrystallizations. In contrast, treatment of 10 with nitroso-
nium tetrafluoroborate in dry CH3CN and iodination of the
corresponding diazonium salt with anhydrous NaI affords
pure monoiodide 6c in 72% yield. The overall yield of this
four-step phenol-to-aryl iodide conversion is 65%. This
method thereby represents an efficient general route for
phenol-to-aryl halide conversion.
Single crystals of synthetic intermediates 3 and 5, N-
methyl pyridinium salts 4′ and 5′, and chromophores TM-1
and TM-2 were obtained via slow evaporation of saturated
solutions.25 The most important feature revealed from the
(15) Munteanu, D.; Csunderlik, C.; Tincul, I. J. Therm. Anal. 1991, 37
(2), 411.
(16) Kang, H.; Facchetti, A.; Zhu, P.; Jiang, H.; Yang, Y.; Cariati, E.;
Righetto, S.; Ugo, R.; Stern, C. L.; Liu, Z.; Ho, S.-T.; Marks, T. J. Angew.
Chem., Int. Ed. In press.
(17) Nucleophilic displacement of activated aryl triflates by malonate:
(a) Atkinson, J. G.; Wasson, B. K.; Fuentes, J. J.; Girard, Y.; Rooney, C.
S.; Engelhardt, E. L. Tetrahedron Lett. 1979, 20, 2857. (b) Williams, H.
W. R.; Rooney, C. S.; Bicking, J. B.; Robb, C. M.; De Solms, S. J.;
Woltersdorf, O. W.; Cragoe, E. J. J. Org. Chem. 1979, 44, 4060.
(18) (a) Uno, M.; Seto, K.; Takahashi, S. J. Chem. Soc., Chem. Commun.
1984, 932. (b) Gao, C.; Tao, X.; Qian, Y.; Huang, J. Chem. Commun. 2003,
1444.
(19) (a) Wiley, G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. J.
Am. Chem. Soc. 1964, 86, 964. (b) Bay, E.; Bak, D. A.; Timony, P. E.;
Leone-Bay, A. J. Org. Chem. 1990, 55, 3415.
(20) (a) Prugh, J. D.; Alberts, A. W.; Deana, A. A.; Gilfillian, J. L.;
Huff, J. W.; Smith, R. L.; Wiggins, J. M. J. Med. Chem. 1990, 33, 758. (b)
Katritzky, A. R.; Li, J.; Stevens, C. V.; Ager, D. J. Org. Prep. Proc. Int.
1994, 26 (4), 439.
(21) (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264. (b)
Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. F. 1997, 62, 1268. (c)
Wolfe, J. P.; A° hman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L.
Tetrahedron Lett. 1997, 38, 6367.
(22) (a) Doyle, M. P.; Siegfried, B.; Dellaria, J. F. J. Org. Chem. 1977,
42, 2426. (b) Kosynkin, D.; Bockman, T. M.; Kochi, J. K. J. Am. Chem.
Soc. 1997, 119, 4846.
(24) Doyle, M. P.; Van Lente, M. A.; Mowat, R.; Fobare, W. F.. J. Org.
Chem. 1980, 45, 2570.
(25) Crystal data for 3: C16H19NO2, M ) 257.32, monoclinic, C2/c, a
) 21.018(6), b ) 8.137(3), c ) 18.221(4) Å, â ) 119.049(12)°, V ) 2724.1-
(13) Å3, Z ) 8, Dc ) 1.255 g/cm3. Of the 12 351 reflections that were
collected, 3314 were independent (Rint ) 0.0351), 177 parameters, R1
)
0.0525 (for reflections with I > 2σ(I)), wR2 ) 0.1552 (for all reflections);
CCDC 274100. Crystal data for 5: C15H17NO, M ) 227.30, orthorhombic,
Fdd2, a ) 21.927(6), b ) 29.244(4), c ) 8.089(2) Å, V ) 5187(2) Å3, Z
) 16, Dc ) 1.164 g/cm3. Of the 11 899 reflections that were collected,
3171 were independent (Rint ) 0.0297), 162 parameters, R1 ) 0.0381 (for
reflections with I > 2σ(I)), wR2 ) 0.1023 (for all reflections); CCDC
274101. Crystal data for 4′: C17H22INO, M ) 383.26, monoclinic, P21/c,
a ) 12.834(2), b ) 17.241(3), c ) 7.9026(13) Å, â ) 100.799(11)°, V )
1717.6(5) Å3, Z ) 4, Dc ) 1.482 g/cm3. Of the 15 777 reflections that
were collected, 4214 were independent (Rint ) 0.0235), 187 parameters, R1
) 0.0288 (for reflections with I > 2σ(I)), wR2 ) 0.0720 (for all reflections);
CCDC 274103. Crystal data for 5′: C16H22INO2, M ) 387.25, monoclinic,
C2/c, a ) 27.251(7), b ) 11.5610(18), c ) 11.868(3) Å, â ) 109.661-
(15)°, V ) 3521.1(13) Å3, Z ) 8, Dc ) 1.461 g/cm3. Of the 15 979
reflections that were collected, 4275 were independent (Rint ) 0.0366), 199
parameters, R1 ) 0.0320 (for reflections with I > 2σ(I)), wR2 ) 0.0840
(for all reflections); CCDC 274102. Crystal data for TM-1: C17H23INNaO2,
M ) 423.25, monoclinic, P21/n, a ) 12.2350(7), b ) 12.9850(7), c )
12.7805(7) Å, â ) 110.2070(8) °, V ) 1905.48(18) Å3, Z ) 4, Dc ) 1.475
g/cm3. Of the 17 558 reflections that were collected, 4664 were independent
(Rint ) 0.0261), 209 parameters, R1 ) 0.0236 (for reflections with I >
2σ(I)), wR2 ) 0.0634 (for all reflections); CCDC 274104. Crystal data for
TM-2: C42H64NO4, M ) 646.94, monoclinic, P21/c, a ) 14.551(2), b )
(23) (a) Hodgson, H. H. Chem. ReV. 1947, 40, 251. (b) Gunstone, F. D.;
Tucker, S. H. Organic Synthesis; Wiley: New York, 1963; Collect Vol.
IV, p 160.
Org. Lett., Vol. 7, No. 17, 2005
3723

Table 1. Selected Crystallographic Data for Twisted π-Electron System Molecules (TMs) and Some Synthetic Intermediates
a 50% probability ellipsoids. Hydrogen atoms and solvent molecules have been omitted for clarity. The iodide counterions are included in the drawings
of 4′ and 5′. b Average of four dihedral angles in the respective crystal structures.
crystallographic analysis of these molecules is the consis-
tently large arene-arene dihedral twist angles (84-88°)
(Table 1), suggesting that the tetra-ortho-methylbiaryl sub-
stitution pattern indeed provides sufficient steric encumbrance
to achieve very large twist angles, a prerequisite for large
molecular hyperpolarizabilities in such TM chromophores.4
Furthermore, it can be seen that the magnitude of this twist
is governed primarily by sterics and is practically independent
of chromophore architecture.26 Indeed, neutral, positively
charged, and zwitterionic molecules all exhibit comparable
twist angles. The (ring)C-C(ring) distances in these mol-
ecules are slightly longer than in typical biaryls (∼1.487 Å),27
doubtless a result of the pronounced steric hindrance. On
the other hand, the (ring)C-C(ring) and (ring)C-O distances
in the two zwitterionic TM chromophores are only modestly
shorter than those of the other species, probably a result of
the very small contribution of quinoidal limit forms to the
ground state, due to the twist-induced intramolecular charge
transfer. Thus, there is a pronounced reduction in inter-ring
π-conjugation and a dominant zwitterionic ground state in
the TM chromophores, evidenced by the departure from
quinoidal structures where (ring)CdC(ring) ≈ 1.349 Å and
CdO ≈ 1.222 Å.27
In summary, synthetic approaches to the first examples
of unconventional twisted π-electron system TM chro-
mophores have been developed. Crystallographic analysis
reveals large ring-ring dihedral twist angles (∼87°) and
highly charge-separated zwitterionic ground states. The
hyperpolarizability physical characteristics will be discussed
elsewhere.
Acknowledgment. We thank DARPA/ONR (SP01-
P7001R-A1/N00014-00-C), the NSF-Europe Program (DMR-
0353831), and the NSF MRSEC program (DMR-0076077)
for support of this research.
15.697(3), c ) 18.554(3) Å, â ) 103.107(2)°, V ) 4127.3(12) Å3, Z ) 4,
Dc ) 1.041 g/cm3. Of the 23 176 reflections that were collected, 5374 were
independent (Rint ) 0.0475), 455 parameters, R1 ) 0.0788 (for reflections
with I > 2σ(I)), wR2 ) 0.2200 (for all reflections); CCDC 274105.
(26) Solid state vs solution 13C NMR and optical absorption spectra of
representative twisted zwitterions containing the same tetra-ortho-methyl-
biaryl substitution pattern argue for comparable twist angles in the solid
state and in solution. See ref 16.
Supporting Information Available: Experimental pro-
cedures, characterization of new compounds, and crystal-
lographic details (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(27) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A.
G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, S1.
OL051365X
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