Hindered rotation in an "exploded" biphenyl

Article abstract of DOI:10.1039/b503173g

The first cases of hindered rotation around the triple bond in simple diphenylacetylenes were observed, including that in chiral 2,2′- bis(trimethylsilyl)-6,6′-bis(dimethylthexylsilyl)-diphenylacetylene. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503173g

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Hindered rotation in an ‘‘exploded’’ biphenyl{
ˇ
´
Ognjen S. Miljanic, Sangdon Han,{ Daniel Holmes, Gaston R. Schaller and K. Peter C. Vollhardt*
Received (in Bloomington, IN, USA) 3rd March 2005, Accepted 21st March 2005
First published as an Advance Article on the web 6th April 2005
DOI: 10.1039/b503173g
Constructs of the type 2a function as building blocks in the
assembly of carbon rich materials, such as planar metalacycles,6
the phenylenes,8 substructures of graphyne and its relatives,9 and
nanotubes.10 The findings of this paper suggest that they might
also be viable as new scaffolds for chiral atropisomeric ligand
construction.11
The first cases of hindered rotation around the triple bond in
simple diphenylacetylenes were observed, including that
in chiral 2,29-bis(trimethylsilyl)-6,69-bis(dimethylthexylsilyl)-
diphenylacetylene.
Tetrasubstituted biphenyls 1 (X ? Y ? H) constitute an intriguing
class of chiral compounds that lack chirogenic centers.1 Their
atropisomerism arises from a) restricted rotation around the axis
of the central single bond, which prevents molecules from equili-
brating with their mirror images, and b) differential substitution,
which makes those mirror images inequivalent. These two
principles are general and can guide the construction of other
chiral systems. A simple case is diphenylacetylene: while the parent
molecule rotates essentially freely around its y4.0 s long –CMC–
unit (DG{ , 1 kcal mol21),2 appropriate substitution should hinder
this motion.2b Rotational isomerism in diaryl- and other alkynes is
of interest fundamentally3 as well as in applications, for example
the design and construction of novel devices4 and polymers.5
Despite these efforts, observable hindered rotation in a simple
diphenylacetylene has remained elusive. Notably, a 2,29,6,69-tetra-
p-tolyl derivative remained conformationally mobile on the NMR
time scale at temperatures as low as 2100 uC.3a
The occurrence of atropisomerism in 2a first became apparent
during the course of the synthesis of the [N]heliphenes, N 5 7–9,
by triple cobalt-catalyzed cycloisomerization of the corresponding
nonaynes.12 In particular, the 500 MHz 1H-NMR spectrum of the
advanced intermediate 3 on route to methoxymethyl [9]heliphene
revealed two doublets (d 5 4.08, 4.15 ppm; AB, J 5 15 Hz) for the
methylene hydrogens at room temperature (500 MHz, CDCl3),
clearly signalling the presence of a configurationally stable chiral
conformation. Furthermore, gradual cooling of the sample to
253 uC in toluene-d8, caused further decoalescence and the
appearance of several broad signals for these hydrogens. At this
temperature, the corresponding methoxy singlet separated into two
distinct peaks (Dn 5 36 Hz), the combined data indicating the
rotational restriction of a second (and perhaps third) stereogenic
axis in the molecule giving rise to two, perhaps three diastereomers.
This communication reports on the NMR-detection of hindered
rotation around the –CMC– unit in alkynylated diphenylacetylenes,
notably core 2b, the simplest member of the class of chiral 2,29,6,69-
tetrakis(alkynyl)diphenylacetylenes 2a.6 These compounds relate
to chiral biphenyls by the simple insertion of a CMC fragment into
all five of the single bonds that bring about the chirality of 1 and
are thus, in Houk–Scott terminology,7 ‘‘exploded’’ biphenyls.
{ Electronic supplementary information (ESI) available: experimental,
spectroscopic, and analytical data for all new compounds. See http://
www.rsc.org/suppdata/cc/b5/b503173g/
{ Present address: Arena Pharmaceuticals, 6166 Nancy Ridge Dr., San
Diego, California 92121, USA.
*kpcv@berkeley.edu
2606 | Chem. Commun., 2005, 2606–2608
This journal is ß The Royal Society of Chemistry 2005

View Article Online
Because of the complexity of the NMR signals of unsymmetrical
3 and to elucidate the nature of these dynamic processes, we turned
to the symmetrical 413 and 5,12 the former as a model for probing
the hindered rotation of the ‘‘outside’’ diphenylacetylene axes ($),
the latter for doing so with respect to their inside counterpart (&).
In these molecules, the signals for the potentially diastereotopic
pairs of methyls of the DMTS group, especially the distinct
silylmethyl absorptions, were sufficiently well resolved to allow for
variable temperature NMR studies.
In 4, a precursor to [7]heliphene by double cyclization,13
restricted rotation may give rise to only two diastereomers: the syn
form, in which the biphenylenyl substituents face each other
(as shown), and the anti rotamer, in which they point in opposite
directions. Molecular mechanics calculations favor the former
Scheme 1 Synthesis of 2b. Reagents and conditions: (i) BuLi, Et2O,
245 uC, 1 h, then I2, Et2O, 245 uC to rt, 2 h, 75% (for 7), 92% (for 9); (ii)
DMTSA, PdCl2(PPh3)2, CuI, NEt3, rt, 20 h, 52%; (iii) TMSA,
PdCl2(PPh3)2, CuI, NEt3, 100 uC, 72 h, 15%.
1
energetically by y1 kcal mol21. At room temperature, the H-
NMR spectrum of 4 displayed two sets of resonances for the two
inequivalent DMTS groups, without any indication of hindered
rotation. Specifically, only two silylmethyl singlets were visible at
d 5 0.12 and 0.16 ppm (400 MHz, CD2Cl2). Upon cooling to
254 uC, the latter decoalesced into two singlets, while the former
started to broaden. The aromatic region of the spectrum remained
unchanged. Similarly, at this temperature, the 13C signals for the
three types of methyl carbons appeared as four lines each, while
the remaining carbons gave rise to single resonances. These
observations are consistent with the occurrence of hindered
rotation around the biphenylenyl–phenyl alkyne bond and the
presence of only one of the two possible diastereomers of 4,
presumably the syn isomer. Simple peak coalescence analysis
provided a barrier of 11.5 kcal mol21 for this process,14 its facility
suggesting that it is also responsible for the lower energy restricted
movement(s) taking place in 3 ($ axes).
To support this hypothesis, a similar analysis was performed on
5. Indeed, decoalescence of the three silylmethyl singlets (d 5 0.04,
0.10, 0.16 ppm, 40 uC) associated with the three distinct DMTS
groups, to six singlets occurred already at 28.1 uC (400 MHz,
CDCl3). Analysis of the decoalescence of the low field signal
furnished an approximate activation barrier of 15.6 kcal mol21 14
.
It therefore seems that the substructure 2a is responsible for the
higher energy conformational process observed in 3 (& axis).
These observations provided the impetus for the synthesis of 2b,
devoid of all the unessential elements present in 3–5. In this system,
there is only one stereogenic axis, and a variable temperature
NMR analysis would provide unambiguous data addressing the
possibility of hindered rotation around a diphenylacetylene triple
bond. The preparation of 2b (Scheme 1) commenced with the
previously described tetrabromodiphenylacetylene 6,6 which was
desymmetrized to 2,29-dibromo-6,69-diiododiphenylacetylene 7 by
bromine–iodine exchange. The iodinated positions in 7 were
alkynylated with DMTSA15 under standard Sonogashira coupling
conditions16 to furnish triyne 8 in 52% yield. A second bromine–
iodine exchange afforded the doubly iodinated 9, the trimethyl-
silylethynylation of which proceeded with great difficulty to give
only 15% of 2b, after a laborious purification sequence that
involved column chromatography, Kugelrohr distillation, and
HPLC.
Fig. 1 1H-NMR (500 MHz) spectra of 2b (methyl group region).
Conditions: a) dioxane-d8, 22 uC; b) THF-d8, 282 uC; c) dioxane-d8,
109 uC, sealed tube.
CDCl3, and THF-d8. The latter (CDCl3) revealed such behavior
only for the carbon-bound methyl groups, the silylmethyl carbons
apparently being accidentally isochronous. In both cases, the
remainder of the spectrum was as expected for a single species.
For the purpose of evaluating the barrier to rotation, the most
diagnostic isopropyl doublets (marked with ‘‘6’’ in Fig. 1) were
chosen. Unfortunately, a solvent covering the entire temperature
range within which spectral changes were occurring could not be
found. Thus, toluene did not provide clear peak separations and
DMF did not dissolve 2b. Therefore, low-temperature NMR
measurements were undertaken in THF-d8, whereas dioxane-d8
was employed at high temperatures. An example of a clearly
resolved low temperature spectrum is shown in Fig. 1b.
Remarkably, restricted rotation was evident already at room-
1
temperature in both the H- and 13C-NMR spectra. The former
featured a doubling of all the signals due to the diastereotopic
methyls of the DMTS group, observable in dioxane-d8 (Fig. 1a),
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2606–2608 | 2607

View Article Online
references); (d) P. K. T. Mew and F. Vo¨gtle, Angew. Chem., Int. Ed.
Engl., 1979, 18, 159.
Coalescence of the isopropyl signals occurred at 96 uC, and
increasing the temperature generated eventually a single set of
DMTS peaks above 100 uC (Fig. 1c). The barrier to enantiomeri-
4 For examples, see: (a) ‘‘Chemosensors’’: J. Raker and T. E. Glass,
J. Org. Chem., 2001, 66, 6505; T. E. Glass, J. Am. Chem. Soc., 2000,
122, 4522; S. Yagi, H. Kitayama and T. Takagishi, J. Chem. Soc.,
Perkin Trans. 1, 2000, 925; (b) ‘‘gyroscopes’’: C. E. Godinez, G. Zepeda,
C. J. Mortko, H. Dang and M. A. Garcia-Garibay, J. Org. Chem.,
2004, 69, 1652; Z. Dominguez, H. Dang, M. J. Strouse and
M. A. Garcia-Garibay, J. Am. Chem. Soc., 2002, 124, 7719;
Z. Dominguez, H. Dang, M. J. Strouse and M. A. Garcia-Garibay,
J. Am. Chem. Soc., 2002, 124, 2398; (c) ‘‘barrow’’: C. Joachim, H. Tang,
F. Moresco, G. Rapenne and G. Meyer, Nanotechnology, 2002, 13, 330;
(d) ‘‘turnstile’’: T. C. Bedard and J. S. Moore, J. Am. Chem. Soc., 1995,
117, 10662.
5 For examples, see: (a) S. Toyota, M. Goichi and M. Kotani, Angew.
Chem. Int. Ed., 2004, 43, 2248; (b) G. Brizius, K. Billingsley, M. D. Smith
and U. H. F. Bunz, Org. Lett., 2003, 5, 3951; (c) M. Levitus,
K. Schmieder, H. Ricks, K. D. Shimizu, U. H. F. Bunz and
M. A. Garcia-Garibay, J. Am. Chem. Soc., 2001, 123, 4259; (d)
T. Miteva, L. Palmer, L. Kloppenburg, D. Neher and U. H. F. Bunz,
Macromolecules, 2000, 33, 652.
6 The parent 2,29,6,69-tetrakis(ethynyl)diphenylacetylene (2a, X 5 Y 5 H)
is known: J. D. Bradshaw, L. Guo, C. A. Tessier and W. J. Youngs,
Organometallics, 1996, 15, 2582.
7 K. N. Houk, L. T. Scott, N. G. Rondan, D. C. Spellmeyer,
G. Reinhardt, J. L. Hyun, G. J. DeCicco, R. Weiss, M. H. M. Chen,
L. S. Bass, J. Clardy, F. S. Jørgensen, T. A. Eaton, V. Sarkozi,
C. M. Petit, L. Ng and K. D. Jordan, J. Am. Chem. Soc., 1985, 107,
6556.
zation in 2b was estimated at 18.7 kcal mol21 14
.
The rotational barrier in 2b is remarkably high, in the high
range of those reported for more complex diarylacetylene systems.
For example, the DG{ values for Toyota’s bis(1-phenyl-9-
anthryl)acetylenes range between 10 and 18 kcal mol21 3b
Moore’s ‘‘molecular turnstiles’’ have corresponding values of 13–
20 kcal mol21 4d
depending on the size of substituents on the aryl
,
while
,
rings. On the other hand, the conformationally mobile 2,29,6,69-
tetrakis(aryl)diphenylacetylene frame exhibits barriers below
8 kcal mol21 3a
, less than a half of that in 2b.
In summary, the first cases of hindered rotation around the
triple bond in simple diphenylacetylenes have been observed,
including that in the simple chiral tetraethynyl system 2b. The
conformational barriers can be substantial, leading to the
observation of restricted rotation by NMR at room temperature.
Future work will aim to gain insight into the effect of substituent
size on the flexibility of 2a with the ultimate goal of achieving
resolution of suitable derivatives. These investigations may lead to
the development of 2a as a viable new tool in chiral scaffold
construction.
ˇ
8 (a) O. S. Miljanic´ and K. P. C. Vollhardt, in Carbon-Rich Compounds:
This work was supported by the National Science Foundation
(CHE-0451241) and the Director, Office of Energy Research,
Office of Basic Energy Sciences, Chemical Sciences Division, of the
U. S. Department of Energy, under Contract DE-AC03-
76SF00098. The Center for New Directions in Organic Synthesis
is supported by Bristol-Myers Squibb as a Sponsoring Member
and Novartis as a Supporting Member.
Molecules to Materials, ed. M. M. Haley and R. R. Tykwinski, Wiley-
VCH, Weinheim, 2005, in press; (b) K. P. C. Vollhardt and
D. L. Mohler, in Advances in Strain in Organic Chemistry, ed.
B. Halton, JAI, London, 1996, vol. 5, p. 121.
9 (a) J. A. Marsden, M. J. O’Connor and M. M. Haley, Org. Lett., 2004,
6, 2385; (b) M. Sonoda, Y. Sakai, T. Yoshimura, Y. Tobe and
K. Kamada, Chem. Lett., 2004, 33, 972; (c) J. M. Kehoe, J. H. Kiley,
J. J. English, C. A. Johnson, R. C. Petersen and M. M. Haley, Org.
Lett., 2000, 2, 969.
10 (a) V. S. Iyer, K. P. C. Vollhardt and R. Wilhelm, Angew. Chem. Int.
Ed., 2003, 42, 4379; (b) P. I. Dosa, C. Erben, V. S. Iyer, K. P. C.
Vollhardt and I. M. Wasser, J. Am. Chem. Soc., 1999, 121, 10430; (c)
R. Boese, A. J. Matzger and K. P. C. Vollhardt, J. Am. Chem. Soc.,
1997, 119, 2052.
11 For reviews see: (a) W. Tang and X. Zhang, Chem. Rev., 2003, 103,
3029; (b) K. Mikami, K. Aikawa, Y. Yusa, J. J. Jodry and
M. Yamanaka, Synlett, 2002, 1561; (c) M. McCarthy and P. J. Guiry,
Tetrahedron, 2001, 57, 3809.
ˇ
´
Ognjen S. Miljanic, Sangdon Han,{ Daniel Holmes, Gaston R. Schaller
and K. Peter C. Vollhardt*
Center for New Directions in Organic Synthesis, Department of
Chemistry, University of California at Berkeley, and the Chemical
Sciences Division, Lawrence Berkeley National Laboratory, Berkeley,
California 94720-1460, USA. E-mail: kpcv@berkeley.edu;
Fax: +1 510 643 5208; Tel: +1 510 642 0286
Notes and references
12 S. Han, D. R. Anderson, A. D. Bond, H. V. Chu, R. L. Disch,
D. Holmes, J. M. Schulman, S. J. Teat, K. P. C. Vollhardt and
G. D. Whitener, Angew. Chem. Int. Ed., 2002, 41, 3227.
13 S. Han, A. D. Bond, R. L. Disch, D. Holmes, J. M. Schulman,
S. J. Teat, K. P. C. Vollhardt and G. D. Whitener, Angew. Chem. Int.
Ed., 2002, 41, 3223.
1 (a) E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of
Organic Compounds, Wiley, New York, 1994, p. 1142; (b) first
observation: G. H. Christie and J. H. Kenner, J. Chem. Soc. Trans.,
1922, 121, 614.
2 (a) J. M. Seminario, A. G. Zacarias and J. M. Tour, J. Am. Chem. Soc.,
1998, 120, 3970; (b) R. Stølevic and P. Bakken, J. Mol. Struct., 1990,
239, 205; (c) A. Grumadas and D. Poskus, Zh. Fiz. Khim., 1987, 61,
2838; (d) K. Okuyama, T. Hasegawa, M. Ito and N. Mikami, J. Phys.
Chem., 1984, 88, 1711.
3 See, inter alia: (a) S. Toyota, T. Iida, C. Kunizane, N. Tanifuji and
Y. Yoshida, Org. Biomol. Chem., 2003, 1, 2298; (b) S. Toyota and
T. Makino, Tetrahedron Lett., 2003, 44, 7775; (c) S. Toyota,
T. Yamamori and T. Makino, Tetrahedron, 2001, 57, 3521 (and cited
¯
14 (a) M. Oki, Applications of Dynamic NMR Spectroscopy to Organic
Chemistry, VCH, Weinheim, 1985; (b) F. P. Gasparro and
N. H. Kolodny, J. Chem. Educ., 1977, 54, 258.
15 M. Mu¨ller, W.-R. Fo¨rster, A. Holst, A. J. Kingma, E. Schaumann and
G. Adiwidjaja, Chem. Eur. J., 1996, 2, 949.
16 K. Sonogashira, in Handbook of Organopalladium Chemistry for
Organic Synthesis, ed. E.-I. Negishi, Wiley, New York, 2002, vol. 1,
p. 493, (and cited references).
2608 | Chem. Commun., 2005, 2606–2608
This journal is ß The Royal Society of Chemistry 2005