Conformational preferences of a polar biaryl: A phase- and enantiomeric purity-dependent molecular hinge

Article abstract of DOI:10.1021/ol9006635

The favored (RS*,M*) diastereoisomer of 2-aryl-pyridine 1 in the solution state results from intramolecular dipole-dipole interactions. In the crystalline state, intermolecular interactions dominate, and the conformation switches reversibly to (RS*,P*). O

Full text of DOI:10.1021/ol9006635

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2313-2316
Conformational Preferences of a Polar
Biaryl: A Phase- and Enantiomeric
Purity-Dependent Molecular Hinge
Jonathan Clayden,* Stephen P. Fletcher, S. J. M. Rowbottom, and
Madeleine Helliwell
School of Chemistry, UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, U.K.
clayden@man.ac.uk
Received March 31, 2009
ABSTRACT
The favored (RS*,M*) diastereoisomer of 2-aryl-pyridine 1 in the solution state results from intramolecular dipole-dipole interactions. In the
crystalline state, intermolecular interactions dominate, and the conformation switches reversibly to (RS*,P*). Only racemic 1 exhibits this
switching property: enantiomerically pure 1 exists as the (RS*,M*) diastereoisomer in both the solution and crystalline state.
Control of mechanical motion at the molecular level is an
area of great contemporary interest.1 A wide variety of
molecular devices including ratchets, switches, shuttles, and
rotors have been developed.2 This work has revealed that
while achieving restricted motion at the molecular level is
not difficult, designing molecular devices that control motion
is much more challenging.
Structures that are shown to move in a unidirectional sense
are of special interest, as it may be possible to harness work
from these machines.2a,3 Mechanisms of unidirectional
control include photochemical isomerization,4 redox events,5
chelation or dative bonding to a transition metal,6 and
selective hydrogen bonding or pH driven processes.7
Devices that control motion in a unidirectional rotary sense
are rarer: Feringa has developed a series of light driven
molecular motors,8 and also reported chemically driven 360°
rotation by combining a series of four 90° events.9 Leigh
has described complex [3]catenane-based motors that achieve
rotation through a sequence of chemical, thermal and
photochemical events.10 Kelly achieved nonreversible 120°
bond rotation in a modified molecular ratchet using phosgene
as the chemical fuel,11 and Haberhauer recently reported a
(5) See the following and literature cited therein: (a) Zhao, Y.-L.;
Aprahamian, I.; Trabolsi, A.; Erina, N.; Stoddart, J. F. J. Am. Chem. Soc.
2008, 130, 6348–6350. (b) Durola, F.; Sauvage, J.-P. Angew. Chem., Int.
Ed. 2007, 46, 3537–3540.
(6) See Barrell, M. J.; Leigh, D. A.; Lusby, P. J.; Slawin, A. M. Z.
Angew. Chem., Int. Ed. 2008, 47, 8036–8039, and references therein.
(7) For example: Bissell, R. A.; Co´dova, E.; Kaifer, A. E.; Stoddart,
J. F. Nature 1994, 369, 133–137.
(1) (a) Balzani, V.; Venturi, M. Credi, A Molecular DeVices and
Machines; Wiley-VCH: Weinheim, Germany, 2003. (b) Topics in Current
Chemistry; Kelly, T. R., Ed.; Springer: Berlin, 2005; Vol. 262.
(2) Selected recent reviews: (a) Browne, W. R.; Feringa, B. L. Nat.
Nanotechnol. 2006, 1, 25–35. (b) Balzani, V.; Credi, A.; Venturi, M.
ChemPhysChem. 2008, 9, 202–220. (c) Kottas, G. S.; Clarke, L. I.; Horinek,
D.; Michl, J. Chem. ReV. 2005, 105, 1281–1376. (d) Kay, E. R.; Leigh,
D. A.; Zerbetto, F. Angew. Chem., Int. Ed. 2007, 46, 72–191. (e) Shirai,
Y.; Morin, J.-F.; Sasaki, T.; Guerrero, J. M.; Tour, J. M. Chem. Soc. ReV.
2006, 35, 1043–1055. (f) Mickler, M.; Schleiff, E.; Hugel, T. ChemPhy-
sChem 2008, 9, 1503–1509.
(8) (a) Koumura, N.; Zijlstra, R. W. J.; van Delden, R. A.; Harada, N.;
Feringa, B. L. Nature 1999, 401, 152–155. (b) Feringa, B. L. J. Org. Chem.
2007, 72, 6635–6652.
(9) Fletcher, S. P.; Dumur, F.; Pollard, M. M.; Feringa, B. L Science
2005, 310, 80–82.
(10) (a) Hernandez, J. V.; Kay, E. R.; Leigh, D. A. Science 2004, 306,
1532–1537. (b) Leigh, D. A.; Wong, J. K. Y.; Dehez, F.; Zerbetto, F. Nature
2003, 424, 174–179.
(3) Diederich, F. Angew. Chem., Int. Ed. 2007, 46, 68–69
.
(11) Kelly, T. R.; De Silva, H.; Silva, R. A. Nature 1999, 401, 150–
152.
(4) Saha, S.; Stoddart, J. F. Chem. Soc. ReV. 2007, 36, 77–92.
10.1021/ol9006635 CCC: $40.75
Published on Web 05/12/2009
 2009 American Chemical Society

hinge that opens and closes (∼180°) unidirectionally based
on addition or removal of Cu(II) to a chiral bipyridine unit.12
Here we report a synthetic structure which undergoes
unidirectional bond rotation when either opening or closing,
in the sense of a molecular hinge. Controlled motion is driven
by a combination of steric restrictions and the thermodynamic
preferences resulting from dipole interactions in two different
states. Simply dissolving or crystallizing the material serves
to change the shape of the potential energy surface of the
system, effecting rotation exclusively in one direction or the
other.
spectroscopy showed that 1 adopts, in solution, the M
conformation, which allows the dipole repulsion between the
aryl C-N and the sulfoxide S-O bonds to be minimized.
Density functional theory (DFT) calculations (Figure 2)
We have shown that dipole-dipole interactions can exert
thermodynamic control over the stereochemistry of atropi-
someric amides,13 diaryl ethers,14 and 2-aryl-pyridines.15
Screening of “conformational auxiliaries” adjacent to atro-
pisomeric, or near-atropisomeric, axes has shown that the
most effective control is obtained with those having the
greatest dipoles, with sulfoxides being particularly effective.13
In the case of sterically hindered conformers or atropisomers,
interconversion of the stereoisomers may be monitored by
1H NMR or circular dichroism spectroscopy at low, ambient,
or elevated temperatures as appropriate. In many cases,
extremely high levels of conformational control (up to
200:1) can be achieved. While we have thus far aimed to
demonstrate the utility of this “dynamic thermodynamic
resolution”13a,14,15 in the synthesis of atropisomerically pure
compounds we were aware that this process could also be
used to power a molecular device.
Figure 2. Fully optimized potential energy scan (B3LYP/6-31G**)
along the dihedral [N-C-C-C(SOAr)] coordinate of 1 using 1b
as a starting point (0 kJ/mol).
As part of a study of the asymmetric synthesis of
QUINAP-like arylisioqiunolines,15 we recently synthesized
the 2-arylpyridine 1. Owing to the presence of the chiral
sulfinyl substituent, 1 can exist in either of two axially
diastereoisomeric conformations, shown in Figure 1 as 1a
furthermore indicated that conformer 1a is 9 kJ mol-1 lower
in energy than conformer 1b in the gas phase.
We have now uncovered conditions in which the opposite
conformation (1b) is exclusively observed. While investigat-
ing the conformation 1 we were initially unable to obtain
crystals from enantiomerically pure material, but the racemate
crystallized readily. In the solid state (()-1 exists exclusively
as diastereoisomer 1b, with opposite relative stereochemistry
to that observed in solution (Figure 3). Assignment of the
solid state conformation is based on single crystal X-ray
analysis of (()-1, with the same crystal form obtained
reproducibly from both DCM/hexane and ether/hexane.
In 2-arylpyridines 1 conformational restraints imposed by
nonbonding interactions between the alkyl group of the
pyridine ring and the sulfinyl group force the conversion of
atropisomers 1a to 1b to occur through rotation in one
direction, and conversion of 1b to 1a to occur exclusively
in the opposite direction. Rotation is driven by thermody-
namically controlled conformational preferences in the
solution phase (favoring 1a) or the solid state (favoring 1b
in the racemate). The shape of the potential energy surface
is changed through adding or removing solvent from the
system16 forcing the biaryl axis to rotate only in one direction
in moving from the solid phase to the solution phase, and
only in the opposite direction in moving from the solution
phase the solid phase.
Figure 1. Conformational preference in 2-aryl-pyridine 1.
and 1b. Slow interconversion between these conformers on
the NMR time scale at achievable temperatures allowed
NMR spectroscopy to show that the compound favors largely
one diastereoisomeric conformation. Circular dichroism
(12) Haberhauer, G. Angew. Chem., Int. Ed. 2008, 47, 3635–3638.
(13) (a) Clayden, J.; Mitjans, D.; Youssef, L. H. J. Am. Chem. Soc.
2002, 124, 5266–5267. (b) Betson, M. S.; Clayden, J.; Helliwell, M.;
Mitjans, D. Org. Biomol. Chem. 2005, 3, 3898–3904. (c) Betson, M. S.;
Clayden, J.; Helliwell, M.; Johnson, P.; Lai, L. W.; Pink, J. H.; Stimson,
C. C.; Vassiliou, N.; Westlund, N.; Yasin, S. A.; Youssef, L. H. Org. Biomol.
Chem. 2006, 4, 424–443.
(14) Clayden, J.; Worrall, C. P.; Moran, W. J.; Helliwell, M. Angew.
Chem., Int. Ed. 2008, 47, 3234–3237.
(15) Clayden, J.; Fletcher, S. P.; McDouall, J. W.; Rowbottom, S. J. M.
J. Am. Chem. Soc. 2009, 131, 5331–5343.
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Org. Lett., Vol. 11, No. 11, 2009

Figure 4.
X-ray crystal structure of (+)-1·1/2H2O showing the
(RS,M) diastereoisomer (water molecule omitted for clarity).
Dihedral angle [N-C-C-C(SOAr)] ) -85.7°.
Figure 3. X-ray crystal structure of (()-1 showing the (RS*,P*)
diastereoisomer. Dihedral angle [N-C-C-C(SOAr)] ) +51.4°.
The ability of the dipole-driven rotor to invert the
thermodynamically favored conformation incorporates re-
versibility into the system, allowing it to act in the sense of
a rotary switch or hinge. While controlled motion is here
driven specifically by changing phases, the results suggest
that controlling motion by altering the thermodynamic
landscape of a rotary system by other methods is feasible.
Conditions which may be more applicable to designing
functional molecular devices,2-7 such as changing solvents,
using additives, or even applying an electric field17 may also
work.
The conformation adopted by 1b in crystals of the
racemate approximates closely to the calculated higher
energy local minimum (Figure 2)sfor example, calculated
dihedral angle [N-C-C-C(SOAr)] ) -51.1°; actual value
) -51.4°. The reason why crystalline (()-1 adopts what is
in the gas phase an inherently unfavorable (by 9 kJ mol-1)
conformation is not clear. Inspection of the crystal packing
suggests that the conformation of (()-1 may be stabilized
by stacking interactions between the pyridine alkyl substit-
uents and the tolyl groups, along with close contact between
the electron-rich oxygen of the sulfoxide and a nearby
relatively acidic (ortho to pyridyl) arene hydrogen atom.18
While (()-1 is a crystalline solid, (+)-1 exists as an oil
which would not crystallize in a closed vessel. However we
found that (+)-1 solidified on extended exposure to air.
Single crystals of (+)-1·1/2H2O were then obtained from
dichloromethane/hexane. Remarkably, in the crystalline state,
(+)-1·1/2H2O was found solely as the (Rs,M) conformation
(1a). Two conformations were found in the unit cell, with
dihedral angles about the biaryl C-C bond of -85.6 and
-62.1°.
The greater stability of the crystalline racemate, despite
the molecules’ adoption of a substantially less favorable
conformation, is suggested by the properties of the two
crystal forms. The density of the racemic crystals was found
to be 1294 kg m-3, while optically pure material was an oil
and (+)-1·1/2H2O has a density of 1282 kg m-3. Comparison
of the melting points of the racemate and optically pure solids
(102-104 and 46-47 °C, respectively) also suggest the
racemic crystals are more stable. Molecules in both crystal
structures adopt conformations which maximize the intramo-
lecular electrostatic interaction between the pyridine nitrogen
and the S-O dipole.18
Compound 1 is thus a rare example of a compound that
may exist as a different diastereoisomer in the solid state
according to whether it is racemic or enantiomerically pure.
Enantiomeric composition is well-known to affect crystal
packing forms19 and differences in conformational prefer-
ence20 have also been observed. In most cases of confor-
mational polymorphism21 the less favorable conformation
is stabilized through hydrogen bonding or close packing
interactions.22 It is however rare for a conformer lying more
than 4.2 kJ mol-1 above the gas phase minimum to be
(19) (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Com-
pounds; Wiley-Interscience: New York, 1994; pp 153-189. (b) Wallach,
O. Liebigs Ann. Chem. 1895, 286, 90–143. (c) Brock, C. P.; Schweizer,
W. B.; Dunitz, J. D. J. Am. Chem. Soc. 1991, 113, 9811–9820.
(20) (a) Saha, I.; Chatterjee, B.; Shamala, N.; Balaram, P. Peptide Sci.
2008, 537–543. (b) de Castro, R. A. E.; Canotilho, J.; Barbosa, R. M.; Silva,
M. R.; Beja, A. M.; Paixa˜, J. A.; Redinha, J. S. E. Cryst. Growth Des.
2007, 7, 496–500. (c) Sainz-D´ıaz, C. I.; Mart´ın-Isla´n, A. P.; Cartwright,
J. H. E. J. Phys. Chem. B. 2005, 109, 18758–18764. (d) Marthi, K.; Larsen,
´
S.; Acs, M.; Fogassy, E. J. Mol. Struct. 1996, 374, 347–355.
(21) (a) Berstein, J. Polymorphism in Molecular Crystals, 1st ed. Oxford
University Press: New York, 2002; p 410. (b) Dunitz, J. D. Pure. Appl.
Chem. 1991, 63, 177–185. (c) Dunitz, J. D. Acta. Crystallogr., Sect. B 1995,
51, 619–631. (d) Wolff, J. J. Angew. Chem., Int. Ed. 1996, 35, 2195–2197.
(e) Nangia, A. Acc. Chem. Res. 2008, 41, 595–604.
(16) For a relevant discussion on the Second Law of Thermodynamics
and the Principle of Microscopic Reversibility see: (a) Davis, A. P. Angew.
Chem., Int. Ed. 1998, 37, 909–910. (b) Kelly, T. R.; Tellitu, I.; Sestelo,
J. P. Angew. Chem. Int. Ed. 1997, 36, 1866–1868. Also see: (c) Davis,
A. P. Nat. Nanotechnol. 2007, 2, 135–136. (d) Serreli, V.; Lee, C.-F.; Kay,
E. R.; Leigh, D. A. Nature 2007, 445, 523–527.
(22) For example see: (a) Smith, J. R.; Xu, W.; Raftery, D. J. Phys.
Chem. B 2006, 110, 7766–7776. (b) Guo, C. Y.; Hickey, M. B.;
Guggenheim, E. R.; Enkelmann, V.; Foxman, B. M. Chem. Commun. 2005,
2220–2222. (c) Brock, C. P.; Minton, R. P. J. Am. Chem. Soc. 1989, 111,
4586–4593. (d) Tel, R. M.; Engberts, J. B. F. N. J. Chem. Soc., Perkin
Trans. 2 1976, 483–488. (e) Bernstein, J.; Hagler, A. T. J. Am. Chem. Soc.
1978, 100, 673–681. (f) Byrn, S. R.; Graber, C. W.; Midland, S. L. J. Org.
Chem. 1976, 41, 2283–2288.
(17) Bermudez, V.; Capron, N.; Gase, T.; Gatti, F. G.; Kajzar, F.; Leigh,
D. A.; Zerbetto, F.; Zhang, S. W. Nature 2000, 406, 608–611.
(18) See Supporting Information.
Org. Lett., Vol. 11, No. 11, 2009
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favored in the crystalline state.23 Exceptions to this occur
when high-energy conformations are stabilized by enhanced
intermolecular interactions,24 stabilizations which are not
obvious from inspection of the crystal structures of 1. The
fact that (+)-1 crystallizes in a hydrated form makes direct
comparison difficult.
Preferential formation of either hetero- or homomultimers
very often explains differences in the behavior of racemic
and enantiopure material.25,26 However, no such interactions
are evident in the crystal structures of (()-1 or (+)-1·1/2H2O.
Here, racemic 1 crystallized in the centrosymmetric space
group P21/n, while (+)-1 is an oil and (+)-1·1/2H2O crystal-
lizes in the chiral space group P3(1). As enantiopure samples
of chiral molecules necessarily crystallize in noncentrosym-
metric space groups it limits the availability of packing
modes (65 out of 230 space groups).19a These differences
in packing ability likely dictate the geometry of the racemic
and optically pure crystals and help explain the apparent
discrepancy of racemic material forming more stable crystals
yet a less stable conformation. Further, the additional
possibilities for favorable packing arrangements available in
achiral space groups, the same symmetry argument used to
explain Wallach’s rule19b by Dunitz,19c may make confor-
mational polymorphism between racemic and enantiomeri-
cally pure compounds fairly common, although this does not
appear to have been explicitly explored in the literature.
The difference in the crystal forms of (()-1 and (+)-1·
1/2H2O creates an unusual situation where the racemic
material acts as a switchable molecular hinge, while the
optically pure material is inactive as a machine. The ability
to use a phase change to modify a potential energy landscape
and achieve reversible unidirectional molecular rotation of
a rotor driven by dipole-dipole interactions represents a new
and powerful way to control the movement of synthetic
molecular devices and suggests that other molecular ma-
chines may also be designed based on this principle.
(23) Allen, F. H.; Harris, S. E.; Taylor, R. J. Comput. Aid. Mol. Des.
1996, 10, 247–254.
(24) (a) Bashkirava, A.; Andrews, P. C.; Junk, P. C.; Robertson, E. G.;
Spiccia, L.; Vanderhoek, N. Chem. Asian J. 2007, 2, 530–538. (b) Starbuck,
J.; Docherty, R.; Charlton, M. H.; Buttar, D. J. Chem. Soc., Perkin Trans.
2 1999, 677–691.
(25) (a) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922–
2959. (b) Heller, D.; Drexler, H.-J.; Fischer, C.; Buschmann, H.; Baumann,
W.; Heller, B. Angew. Chem., Int. Ed. 2000, 39, 495–499. (c) Blackmond,
D. G.; Klussmann, M. AIChE 2007, 53, 2–8
.
(26) For example: the diastereoselectivity of a reaction can depend on
the enantiomeric composition of the starting reactant, see ref 25 and (i) in
solution: (a) Wynberg, H.; Feringa, B. Tetrahedron 1976, 32, 2831–8234.
(b) Feringa, B.; Wynberg, H. J. Am. Chem. Soc. 1976, 98, 3372–3373. (c)
Rautenstrauch, V.; Megard, P.; Bourdin, B.; Furrer, A. J. Am. Chem. Soc.
1992, 114, 1418–1428. (d) Paquette, L. A.; Romine, J.; Barth, W.; Hsu,
L.-Y. Tetrahedron Lett. 1985, 26, 567–570. (e) Thottathil, J. K.; Przybyla,
C.; Malley, M.; Gougoutas, J. Z. Tetrahedron Lett. 1986, 27, 1533–1536(ii)
On the surface of electrodes: (f) Touboul, E.; Dana, G. Tetrahedron 1975,
31, 1925–1931. (g) Touboul, E.; Dana, G. J. Org. Chem. 1979, 44, 1397–
1404. (h) Paquette, L. A.; Itoh, I.; Farnham, W. B. J. Am. Chem. Soc. 1975,
Acknowledgment. We are grateful to the EPSRC for
support of this work.
Supporting Information Available: Characterization and
crystallographic data for 1a and 1b. This material is available
free of charge via the Internet at http://pubs.acs.org.
97, 7280–7285
.
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