Effect of diazocine bridgehead modification on the folding of the wilcox molecular torsion balance: A view from a different angle

Article abstract of DOI:10.1021/jo200316t

Replacing the methano (NCH₂N) bridgehead with an ethano (NCH₂CH₂N) bridgehead affects the conformational equilibrium of the Wilcox molecular torsion balance. With a NCH ₂CH₂N bridgehead, the phenyl an

Full text of DOI:10.1021/jo200316t

NOTE
pubs.acs.org/joc
Effect of Diazocine Bridgehead Modification on the Folding of the
Wilcox Molecular Torsion Balance: A View from a Different Angle
Brijesh Bhayana† and Mark R. Ams*,‡
‡Department of Chemistry, Allegheny College, 520 North Main Street, Meadville, Pennsylvania 16335-3902, United States
†Wellman Center for Photomedicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, United States
S Supporting Information
b
ABSTRACT: Replacing the methano (NCH2N) bridgehead with an
ethano (NCH2CH2N) bridgehead affects the conformational equilib-
rium of the Wilcox molecular torsion balance. With a NCH2CH2N
bridgehead, the phenyl and the cyclohexyl esters prefer the out
conformation, whereas with the NCH2N bridgehead, they were found
to prefer the folded conformation.
he Wilcox torsion balance was introduced nearly two decades
ago as a tool for measuring weak edge-to-face aromatic
T
interactions that would normally be difficult to quantify.1 Such
interactions are ubiquitous in chemistry and biology and are
involved in wide-ranging phenomena such as protein folding,
DNA replication, chiral discrimination, stereoselective synthesis,
molecular recognition, self-assembly, crystal packing, and metal
coordination to name a few.2 An elegant feature of the torsion
balance is its simple design, consisting of a gently rotating
functionalized phenyl ring mounted on a V-shaped rigid framework
of Tr€oger’s base. The two ortho-substituents on the phenyl ring
provide a rotational barrier high enough for two atropisomers to be
observed distinctly by NMR spectroscopy at room temperature. It
was found that the folded (in) conformation in which the ester
resides above the arene was preferred over the out conformation by
a free energy difference of 0.2ꢀ0.8 kcal/mol, and that electron-
withdrawing or -donating substituents on the bottom arene had little
effect on the folding ratio. These observations were originally thought
to be consistent with the predominantly dispersive nature of the
CHꢀπ interactions, but subsequent studies have shown that the
trends in folding behavior of these molecules can also be explained by
a delicate balance of solvent and electrostatic interactions.3
Figure 1. Gaussian geometry optimization predictions of ethano (left)
and methano (right) strapped Tr€oger’s base.
shorter CHꢀπ interaction distance and its folding ratio could
provide valuable information on how this interaction scales with
distance. Herein, we describe the folding behavior of a new
molecular torsion balance that contains a bridgehead modifica-
tion from methyl to ethyl (Figure 2).
Several new torsion balances bearing the NCH2CH2N bridge-
head were synthesized via Suzuki-coupling (Scheme 1), and their
corresponding folding ratios measured by 1H NMR spectroscopy.5,6
The folding ratios revealed an interesting trend. The folding
energies (ΔGethyl°) for the ethano-bridged torsion balances
(methyl, isopropyl and tert-butyl) were close to the values
observed for the corresponding methano-bridged torsion bal-
ances (ΔGmethyl°). Although the differences between the folding
energies (ΔΔG° = ΔGethyl° ꢀ ΔGmethyl°, ∼0.1 kcal/mol) in the
methano vs ethano balances are small for these esters, the results
do not automatically imply that the CHꢀπ interaction was
unaltered. This is because the conformational equilibrium is
An architectural feature common to the torsion balances
reported to date is the methano (NCH2N) bridgehead, which
imposes an almost T-shaped geometry between the ester CH
bonds and the bottom arene. Despite the general rigidity, the
dihedral angle between the planes of the two aromatic rings of the
Tr€oger’s base have been observed to vary from 86° to 104° in
X-ray crystal structures of various analogues.4 Interestingly, both
crystal-structure data and geometry-optimization studies show a
significant decrease, up to 20° in some cases, in the dihedral angle
when an ethano bridgehead is used instead (Figure 1).5
On the basis of this observation, we surmised that a torsion
balance with an ethanodibenzodiazocine framework will have a
Received: February 23, 2011
Published: March 16, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200316t J. Org. Chem. 2011, 76, 3594–3596
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The Journal of Organic Chemistry
NOTE
Scheme 1
Figure 3. Solid-state structure of a phenyl-ester torsion balance re-
ported by Wilcox and co-workers (reprinted with permission from ref
1a; copyright 1994, American Chemical Society).
orthoganol dipolar interaction between amide carbonyls and an
amideꢀCF3 interaction (see ref 3). A bridgehead modification in
such studies can be a useful tool for altering the interaction distance.
Figure 2. Folding ratios of methano- and ethano-bridged torsion
balances (kcal/mol, in CDCl3 at 298K, ( 10%). aReported by Wilcox
in reference 1a,b.
’ EXPERIMENTAL SECTION
determined by the overall sum of many different individual
energetic contributions such as those arising from dispersion
interactions, electronic, steric, and solvation effects. An increase
in the attractive CHꢀπ component accompanied with a corre-
sponding increase in repulsive interactions (such as steric effects)
can also result in a small ΔΔG°. Chemical calculations can shed
more light on how individual energetic contributions are affected
by bridgehead modification. Therefore, these results may be of
interest to computational chemists.
The conformational equilibria of the phenyl and cyclohexyl
esters are more intriguing. For these balances, the ΔΔG° is much
larger (∼0.4 kcal/mol) and in favor of the out conformation.
Since these esters have a more extended contact area with the
bottom arene compared to the isopropyl and tert-butyl esters, a
bigger ΔΔG° may be expected. A preference for the out
conformation suggests that steric repulsions dominate over the
attractive interactions. The solid state structures of the phenyl
ester torsion balances by Wilcox show a close contact distance
between the meta hydrogen atom on the ester ring (A in
Figure 3) and the bottom arene. In our study, the replacement
of the methano bridgehead with an ethano bridgehead could
decrease the interaction distance and therefore increase steric
repulsions in this region. The end result is a denatured balance
that avoids the steric clash.
All reagents were purchased from commercial suppliers and used
1
without further purification. H and 13C spectra were recorded on a
300 MHz NMR spectrometer. The spectra are referenced internally to
the residual proton resonance in CDCl3 (δ = 7.26 ppm). The 13C
spectra are referenced to CDCl3 (δ = 77.0 ppm). The coupling
constants are reported in hertz (Hz). Thin layer chromatography was
performed on silica gel 60 F254 plates. The pinacolatoboronate ester of
ethanodibenzodiazocine was synthesized by using known procedures.5
Representative Procedure for the Suzuki-Coupling Reac-
tion. A 6 mL screw cap glass vial equipped with a magnetic stir bar and a
plastic screw cap with Teflon septum was charged with tert-butyl
2-bromo-3-methylbenzoate (27.0 mg, 0.1 mmol), 2-methyl-8-(4,4,5,
5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,12-dihydro-5,11-ethanodiben-
zo[b,f][1,5]diazocine (37.0 mg, 0.10 mmol), Pd(OAc)2 (1.1 mg, 0.005
mmol), and dicyclohexyl(20,60-dimethoxy-[1,10-biphenyl]-2-yl)pho-
sphine (SPhos, 4.1 mg, 0.01 mmol). After these additions, the vial was
purged with argon and 0.2 mL of acetonitrile (HPLC grade), then
0.1 mL of 2.0 M K2CO3 was added to it with a syringe. The reaction
mixture was then stirred at 80 °C for 2 h and cooled to room tem-
perature, then the reaction solution was layered on a TLC plate.
Purification by using prep TLC (ethyl acetate:hexanes, 1:3) provided
the desired product 2b (21 mg, 48% yield) as a thick light yellow oil.
NMR Characterization. Isopropyl 3-methyl-2-(8-methyl-6,12-
dihydro-5,11-ethanodibenzo[b,f][1,5]diazocin-2-yl)benzoate (2a): 1H
NMR δ 7.55ꢀ7.50 (m, 1H), 7.33ꢀ7.2 (m, 2H), 7.12ꢀ7.05 (m, 1H),
7.0ꢀ6.95 (m, 1H), 6.93ꢀ6.8 (m, 2H), 6.75ꢀ6.65 (m, 2H), 4.89ꢀ4.35
(m, 5H), 3.66ꢀ3.50 (m, 4H), 2.16 (s, br, 3H), 2.04/1.85 (s, 3H, 2.8/1),
0.96/0.33 (d, J = 6.2 Hz, 3H, 1/2.8), 0.94/0.27 (d, J = 6.2 Hz, 3H, 1/2.8).
13C NMR δ 168.9, 149.0, 147.6, 147.5, 140.2, 137.1, 136.8, 136.6, 136.2,
134.1, 133.9, 133.0, 132.9, 132.5, 132.3, 129.2, 128.8, 128.0, 127.86,
127.83, 127.6, 127.5, 127.4, 127.0, 126.9, 126.4, 124.6, 68.1, 59.18, 59.12,
In conclusion, our data suggest that replacing the methano
bridgehead with an ethano bridgehead in the Wilcox torsion
balance leads to a decrease in the esterꢀarene interaction
distance. We believe that like previously, the data from this study
will be of value to researchers interested in modeling weak
interactions and solvation effects.7 The torsion balance has been
used by Diederich to study nonbonding interactions such as the
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The Journal of Organic Chemistry
NOTE
55.0, 54.9, 54.8, 54.7, 21.38, 21.31, 20.7, 20.6, 20.47, 20.43. HRMS m/e
calcd for C28H30N2O2 426.2307, found 426.2322.
(d) Fischer, F. R.; Schweizer, W. B.; Diederich, F. Chem. Commun. 2008,
34, 4031.
(4) (a)Wilcox, C. S. Tetrahedron Lett. 1985, 26, 5749. (b) Sucholeiki, I.;
Lynch, V.; Phan, L.; Wilcox, C. S. J. Org. Chem. 1988, 53, 98. (c) Adrian,
J. C., Jr.; Wilcox, C. S. J. Am. Chem. Soc. 1992, 114, 1398.
(5) (a) Faroughi, M.; Zhu, K. X.; Jensen, P.; Craig, D. C.; Try, A. C.
Eur. J. Org. Chem. 2009, 25, 4266. (b) Sergeyev, S. Helv. Chem. Acta
2009, 29 (3), 415. (c) Faroughi, M.; Try, A. C.; Klepetko, J.; Turner, P.
Tetrahedron Lett. 2007, 48, 6548. (d) Ishida, Y.; Ito, H.; Mori, D.; Saigo,
K. Tetrahedron Lett. 2005, 46, 109. (e) Hamada, Y.; Mukai, S.
Tetrahedron: Asymmetry 1996, 7, 2671.
(6) See the Experimental Section and the Supporting Information
for details. For Suzuki couplings, see: Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
(7) (a) Nakamura, K; Houk, K. N. Org. Lett. 1999, 1, 2049.
(b) Cockroft, S. L.; Hunter, C. A. Chem Commun. 2009, 26, 3961.
tert-Butyl 3-methyl-2-(8-methyl-6,12-dihydro-5,11-ethanodibenzo[b,f]
[1,5]diazocin-2-yl)benzoate (2b): 1H NMR δ 7.5ꢀ7.4 (m, 1H),
7.35ꢀ7.17 (m, 2H), 7.15ꢀ7.11 (m, 1H), 7.0ꢀ6.95 (m, 1H), 6.9ꢀ6.8
(m, 2H), 6.75ꢀ6.65 (m, 2H), 4.68ꢀ4.35 (m, 4H), 3.68ꢀ3.50 (m, 4H),
2.18 (s, br, 3H), 2.03/1.86 (s, 3H, 3.6/1), 1.19/0.67 (s, 9H, 1/3.6). 13C
NMR δ 168.6, 148.9, 147.6, 139.9, 136.9, 136.7, 136.3, 136.2, 134.2,
134.1, 131.9, 129.0, 128.6, 128.2, 128.1, 128.03, 127.8, 127.4, 126.9,
126.2, 80.8, 80.6, 59.18, 59.12, 54.99, 54.95, 27.57, 27.0, 20.6, 20.3.
HRMS m/e calcd for C29H32N2O2 440.2464, found 440.2453.
Phenyl 3-methyl-2-(8-methyl-6,12-dihydro-5,11-ethanodibenzo
[b,f][1,5]diazocin-2-yl)benzoate (2c): 1H NMR δ 7.72/7.65 (d, J = 7.0
Hz, 1H, 1.3/1), 7.5ꢀ6.7 (m, 12H), 6.26 (m, 1H), 4.68ꢀ4.2 (m, 4H),
3.77ꢀ3.50 (m, 4H), 2.18 (s, br, 3H), 2.1/1.9 (s, 3H, 1.3/1). 13C NMR
δ 166.8, 150.1, 148.7, 146.9, 140.6, 136.8, 135.9, 135.7, 133.3, 132.7,
132.5, 131.0, 128.6, 128.3, 128.2, 127.3, 127.2, 127.0, 126.49, 126.45,
125.0, 124.5, 120.7, 120.4, 58.6, 58.4, 54.4, 54.2, 20.3, 20.1, 19.7. HRMS
m/e calcd for C31H28N2O2 460.2151, found 460.2137.
Cyclohexyl 3-methyl-2-(8-methyl-6,12-dihydro-5,11-ethanodibenzo-
[b,f][1,5]diazocin-2-yl)benzoate (2d): 1H NMR δ 7.56/7.49 (d, J = 6.6
Hz, 1H, 1.14/1), 7.3ꢀ7.2 (m, 2H), 7.12ꢀ7.08 (m, 1H), 6.99ꢀ6.8 (m,
3H), 6.75ꢀ6.6 (m, 2H), 4.7ꢀ4.3 (m, 5H), 3.77ꢀ3.50 (m, 4H), 2.18 (s,
br, 3H), 2.04/1.83 (s, 3H, 1.13/1), 1.6ꢀ0.3 (m, 10H). 13C NMR
δ 168.6, 148.9, 147.5, 140.5, 140.1, 137.17, 137.12, 136.6, 136.5, 136.4,
136.3, 136.2, 133.9, 132.9, 132.4, 132.2, 129.19, 129.15, 128.8, 128.7,
128.5, 127.99, 127.92, 127.91, 127.8, 127.7, 127.6, 127.5, 127.49, 127.44,
127.3, 126.8, 126.6, 126.3, 73.0, 72.9, 59.2, 59.1, 59.04, 59.02, 58.9, 55.1,
55.0, 54.9, 54.8, 54.76, 31.1, 30.5, 30.3, 25.3, 25.2, 23.6, 23.3, 23.1, 20.3.
HRMS m/e calcd for C31H34N2O2 466.2620, found 466.2622.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
compound characterization for all new compounds. This materi-
al is available free of charge via the Internet at http://pubs.acs.
org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mams@allegheny.edu.
’ ACKNOWLEDGMENT
The authors acknowledge Allegheny College for financial
support of this research.
’ REFERENCES
(1) (a) Paliwal, S.; Geib, S.; Wilcox, C. S. J. Am. Chem. Soc. 1994,
116, 4497. (b) Kim, E.-I.; Paliwal, S.; Wilcox, C. S. J. Am. Chem. Soc.
1998, 120, 11192. (c) Bhayana, B.; Wilcox, C. S. Angew. Chem., Int. Ed.
2007, 46, 6833.
(2) (a) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem.,
Int. Ed. 2003, 42, 1210. (b) Gazit, E. FASEB J. 2002, 16, 77. (c) Frank,
B. S.; Vardar, D.; Buckley, D. A.; McKnight, C. J. Protein Sci. 2002,
11, 680. (d) McGaughey, G. B.; Gagne, M; Rappe, A. K. J. Biol. Chem.
1998, 273, 15458–15463. (e) Burley, S. K.; Petsko, G. A. Science 1985,
229, 23.
(3) Reference 1 and: (a) Cockroft, S. L.; Hunter, C. A. Chem.
Commun. 2009, 26, 3961. (b) Fischer, F. R.; Schweizer, W. B.; Diederich,
F. Angew. Chem., Int. Ed. 2007, 46, 8270. (c) Fischer, F. R.; Wood, P. A.;
Allen, F. H.; Diederich, F. Proc. Natl. Acad. Sci. 2008, 105 (45), 17290.
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