Wilcox molecular torsion balance with rigid side arm and separable atropisomers for investigating CH-π interactions

Article abstract of DOI:10.1021/jo400782e

A new variant of the Wilcox molecular torsion balance featuring a naphthyl-alkyl side arm was synthesized. The energy barrier for axial isomerization in the new balance was sufficiently high to allow for separation of the two rotamers and to observe their isomerization kinetics. The CH-π interaction energies in derivatives of the new and the original ester balance were in close agreement, suggesting that the motion in ester linkage is not an important factor in folding in the ester balance.

Full text of DOI:10.1021/jo400782e

Note
pubs.acs.org/joc
Wilcox Molecular Torsion Balance with Rigid Side Arm and Separable
Atropisomers for Investigating CH−π Interactions
Brijesh Bhayana*
Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, Massachusetts 02114, United States
S
* Supporting Information
ABSTRACT: A new variant of the Wilcox molecular torsion balance
featuring a naphthyl-alkyl side arm was synthesized. The energy
barrier for axial isomerization in the new balance was sufficiently high
to allow for separation of the two rotamers and to observe their
isomerization kinetics. The CH−π interaction energies in derivatives
of the new and the original ester balance were in close agreement,
suggesting that the motion in ester linkage is not an important factor
in folding in the ester balance.
he molecular torsion balance developed by Wilcox and co-
equilibration process to inconveniently long times. It was therefore
Tworkers has been used in a number of studies for quantification necessary to equilibrate the balances at elevated temperatures prior
of various weak noncovalent interactions.1−9 Within the torsion
to their NMR analysis at 298 K. In DMSO-d6 as solvent, the
equilibration temperature had negligible effect onthe folding ratios
in the temperature range of 70−140 °C,19 which validated the use
of the equilibration method for determination of room temper-
ature ΔGf°old values. In addition to the effect of temperature, the
effect solvent on folding energy was also investigated. The ΔGf°old
values were nearly identical in chloroform, 1,2-dichloroethane, and
DMSO.20 The folding ratios of Wilcox’s ester balances were also
found to be unaffected by solvent (e.g., DMSO, chloroform,
acetone, CH2Cl2, nitromethane) ortemperature.1,2 Theconforma-
tional equilibrium inthe new and the original balance is thus driven
by similar factors.
Within the new balance, the methyl ether showed a small
preference for the unfolded state (ΔG°fold = +0.27 kcal/mol). The
larger alkyl groups preferred the folded state, indicating the
presence of attractive CH−π interactions (Table 1). The new
balance was therefore suitable for quantifying such interactions.
The folding energies (ΔGf°old) of various ethers at 298 K were in
the range of 0.4−0.5 kcal/mol,21 which were close to the ΔG°fold
values reported by Wilcox (0.3−0.5 kcal/mol) for analogous
esters (Table 1).1−3,7 The close similarity in folding energies of
the new and the original derivatives was interesting given that
they had different side arms. The ester side arm has a greater
conformational flexibility since the dihedral angle between the
top aromatic ring and the ester C(O)O plane is adjustable. Ab
initio calculations suggest that, in the ester balance, the C(O)O
plane of the ester should be significantly twisted out of plane with
respect to the top aromatic ring in the minimum energy
configuration.22 Solid-state structures of the ester balances available
in literature also support this view.1,6 In contrast, the side arm in the
new balance is essentially planar. The similarity in the folding
energies therefore suggests that the motion in the ester linkage is not
balance, the folding energy is easily determined via NMR spectros-
copy; however, the rapid exchange between balance’s folded and
unfolded states on the NMR time scale has hindered the ability to
isolate its two rotamers and study their folding kinetics.10 Such
studies are important for extending the utility of the torsion
balance strategy. For example, with a separable torsion balance,
factors affecting energy barrier for atropisomerization in hindered
biaryl systems can be studied.11−15 Alternatively, high rotational
barriers could allow separate characterization of the folded and
unfolded conformers by X-ray crystallographic analysis. Such
potential applications provided the impetus for developing a
torsion balance with separable atropisomers.
In the design of the new balance, various alternatives were available
for increasing the rotational barrier. However, the substitution of the
ester side arm with a naphthyl-alkyl ether side arm was particularly
appealing. Unlike the ester linker, the naphthyl ether linker imposed a
much more restricted geometry on the interacting fragment while
presenting it to the bottom arene. A comparison of folding ratios of
the new and the original balance then also allowed for elucidation of
effects of motion in the ester linker on CH−π interactions in the
original balance. A balance with a naphthyl-alkyl ether side arm was
thus chosen as the target candidate for synthesis.
The synthesis of the derivatives of the new balance (Scheme 1)
were accomplished via Suzuki coupling between pinacol
boronate ester of Troger’s base derived from 4-bromo-2,5-
dimethylaniline and the triflates of the monoalkyl ethers of
naphthalene-1,8-diol.16−18 The folded and unfolded conformers
were separable via silica gel chromatography and were quite
stable toward atropisomerization at room temperature. With the
exception of the methyl ether balance, the new balances showedno
trace of axial isomerization even after several days in solution at
room temperature. While the axial stability was advantageous for
separation purposes, it also hindered the ability to measure the
folding energy (ΔG°fold) at room temperature as it slowed the
Received: April 12, 2013
Published: June 11, 2013
© 2013 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 1. Synthesis of the New Torsion Balances
Figure 1. Isomerization kinetics (T = 47 °C) of conformers 1a, 1b, and 3a. Solid lines show the simulated equilibration curves with rate constant values
of kfold→unfold = 0.05 h−1 and kunfold→fold = 0.035 h−1.
an important factor in folding in the ester balance, and that the
torsion balance CH−π interaction energies are general rather than
reflecting the specifics of a particular structural framework.
Table 1. Folding Ratios and Folding Energies of the
Derivatives of the New Balance
balance (R)
% folded at equilibrium
ΔGf°old (kcal/mol)
The study of folding kinetics is essential for deciphering the
effects of dynamic solvent influences on solute’s conformational
changes and estimation of activation parameters. The folding
kinetics of the folded and unfolded conformers was studied by NMR
spectroscopy, and their activation energies for atropisomerization
were determined. Upon warming, both conformers reached the
same equilibrium state. The rate of atropisomerization was found to
decrease with the increase in the size of the alkoxy group. As seen in
Figure 1, while the folded and the unfolded conformers of methyl
ether balance reached the equilibrium state in approximately 50 h at
47 °C, almost no atropisomerization was observed for the bulkier
cyclopentyl ether balance under the same conditions. The rate
a
b
CH3
38
62
59
59
+0.27 [0.0]
c
b
b
b
CH(CH3)2
c-Pent
−0.55 [−0.44]
c
−0.48 [−0.35]
c
c-Hex
−0.48 [−0.37]
a
Calculated at 298 K after equilibrating the balance at 80 °C followed
by NMR analysis at 298 K. ΔG°fold,methyl ether = −RT ln([folded]/[unfolded]).
b
c
Folding energy of the analogous ester balance. Calculated as ΔG° =
−RT ln([folded]/[unfolded]) − ΔGf°old,methyl ether
.
the Eyring equation furnishing the energy barrier for atropisome-
rization. ΔG⧧ values of ≈26 kcal/mol (T = 47 °C) and ≈27 kcal/mol
(T = 80 °C) were estimated for the methyl (Figure 1) and the
isopropyl ether (Figure 2), respectively.
constants for unfolding (kfold→unfold) and folding (kunfold→fold
)
processes were estimated by comparing the experimental data
with the results of the numerical simulation of the rate equations.23
At equilibrium, these rate constants satisfy the rate constants with
In addition to the ether balance, an ester balance (5a,b;
Scheme 1) containing three ortho substituents along the biaryl
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The Journal of Organic Chemistry
Note
Figure 2. Isomerization kinetics (T = 80 °C) of conformers 2a and 2b. Solid lines show the simulated equilibration curves with rate constant values of
kfold→unfold = 0.25 h−1 and kunfold→fold = 0.38 h−1.
inspection. The energy barriers for atropisomerization (ΔG⧧) were
axis was also synthesized using the standard Suzuki coupling
strategy. The conformers of this balance showed no axial
isomerization even after heating at 100 °C for 20 h, indicating a
calculated using the rate constant values of the best fits in the Eyring
equation: k = (kBT/h) × exp[−ΔG⧧/RT].
much higher rotational barrier. Conformational stability and
well-defined architecture could make this kind of balance
potentially useful for newer applications.
In conclusion, incorporation of a naphthyl-alkyl ether side arm
in the torsion balance allowed for the separation of the folded and
unfolded conformers and recording of their folding kinetics for
the first time. The ability to separate the two atropisomers and
study their conformational dynamics will greatly increase the
scope of application of the Wilcox balance.
Representative Procedure for the Suzuki Coupling Reaction.
A 6 mL glass vial equipped with a magnetic stir bar and a Teflon screw
cap was charged with 8-methoxynaphthalen-1-yl trifluoromethane-
sulfonate (61 mg, 0.2 mmol), 1,4,7,10-tetramethyl-2-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-6,12-dihydro-5,11-methanodibenzo-
[b,f ][1,5]diazocine (101 mg, 0.25 mmol), Pd(OAc)2 (1.1 mg, 0.005 mmol),
and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine
(SPhos, 4.1 mg, 0.01 mmol). After these additions, the vial was purged
with argon and 0.5 mL of acetonitrile (HPLC grade), followed by
0.5 mL of 2.0 M Na2CO3, was added to it with a syringe. The reaction
mixture was then stirred at 80 °C for 4 h in an aluminum block, cooled to
room temperature, and then purified using silica gel chromatography
(ethyl acetate−hexanes gradient) to yield 1a and 1b as amorphous
solids.
EXPERIMENTAL SECTION
■
1H NMR spectra were recorded on a 300 MHz spectrometer, and
resonances are given in parts per million relative to the residual solvent
resonance (CHCl3 δ 7.26, (CH3)2SO δ 2.54). 13C NMR spectra were
recorded at 75 MHz and are referenced to the residual solvent (CDCl3
δ 77.0 ppm). High-resolution mass spectra (HRMS) were recorded in
the electrospray ionization (ESI) mode on a TOF mass analyzer. IR
resonances are given in cm−1.
2-(8-Methoxynaphthalen-1-yl)-1,4,7,10-tetramethyl-6,12-di-
hydro-5,11-methanodibenzo[b,f][1,5]diazocine (1a): Yield 21 mg
1
(24%); H NMR (300 MHz, CDCl3) (folded) δ 7.76 (dd, J = 1.2 and
8.2 Hz, 1H), 7.5−7.4 (m, 2H), 7.35−7.2 (m, 2H), 7.0 (d, J = 8.2 Hz, 1H),
6.99 (m, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.6 (dd, J = 1.2 and 8.2 Hz, 1H),
4.5−4.3 (m, 4H), 4.1−4.0 (m, 2H), 2.89 (s, 3H), 2.46 (s, 3H), 2.43
(s, 3H), 2.1 (s, 3H), 1.65 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.6,
146.3, 144.4, 140.5, 138.2, 135.4, 132.6, 130.7, 129.9, 129.0, 128.4, 128.2,
128.0, 127.3, 126.5, 125.7, 125.6, 124.9, 124.8, 124.3, 121.2, 105.8, 66.5,
54.8, 54.3, 54.2, 17.8, 17.1, 14.9; IR 2941, 1506, 1474, 1462, 1373, 1307,
1258, 1219, 1071, 963, 946, 885; HRMS-ESI [M + H]+ calcd for
C30H31N2O+ 435.2431, found 435.2430.
2-(8-Methoxynaphthalen-1-yl)-1,4,7,10-tetramethyl-6,12-di-
hydro-5,11-methanodibenzo[b,f][1,5]diazocine (1b): Yield 35
mg (40%); 1H NMR (300 MHz, CDCl3) (unfolded) δ 7.76 (dd, J = 1.1
and 8.2 Hz, 1H), 7.5−7.3 (m, 3H), 7.07 (dd, J = 1.2 and 7.1 Hz, 1H),
7.02−6.99 (m, 1H), 6.88 (s, br, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.75 (d, J =
7.5 Hz, 1H), 4.47 (dd, J = 8.8 and 16.8 Hz, 2H), 4.35 (s, br, 2H), 4.01
(t, J = 16.3 Hz, 2H), 3.48 (s, 3H), 2.42 (s, 6H), 2.12 (s, 3H), 1.65 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 156.9, 146.5, 144.1, 140.6, 138.3,
135.4, 132.8, 130.4, 130.3, 129.2, 128.5, 128.4, 127.9, 127.1, 126.8, 125.7,
125.5, 125.0, 124.5, 124.3, 121.2, 106.0, 66.5, 55.7, 54.1, 53.6, 17.8, 17.0,
16.9, 14.8; IR 2939, 1506, 1474, 1460, 1374, 1304, 1257, 1219, 1071,
963, 946, 878; HRMS-ESI [M + H]+ calcd for C30H31N2O+ 435.2431,
found 435.2430.
Representative Procedure for Kinetic Isomerization and
Determination of Rate Constants. A NMR tube containing a
sample of a pure compound dissolved in DMSO-d6 was placed in a
heated aluminum block maintained at a fixed temperature. The sample
tube was withdrawn at different intervals of time and cooled to the room
temperature in a water bath, and the NMR spectra were recorded. The
equilibrium folding ratio was determined by keeping the sample in the
heat bath for a prolonged period of time (several days at 70 °C or 4 h at
140 °C) and checking for constancy in the isomer ratio. The plots for the
experimental data were generated in the MS Excel program. In the
COPASI program, irreversible first-order rate law equations for folding
and unfolding processes, initial concentration values ([Cfolded]0,
[Cunfolded]0), and the guess values for the rate constants kfold→unfold and
kunfold→fold were entered according to the software’s input format. The
values of rate constants were chosen such that the equilibrium condition
kfold→unfold[Cfolded
]
= kunfold→fold[Cunfolded
]
eq
was satisfied with good
eq
precision. For given kfold→unfold and kunfold→fold values, simulation curves
were generated for both folding and unfolding processes. These curves
were copied and stacked over the experimental data plots in the Excel
spreadsheet. The rate constant values in COPASI were varied until the
simulation curves matched the experimental data as judged by visual
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Note
2-(8-Isopropoxynaphthalen-1-yl)-1,4,7,10-tetramethyl-6,12-di-
hydro-5,11-methanodibenzo[b,f ][1,5]diazocine (2a): Yield 20 mg
(22%); 1H NMR (300 MHz, CDCl3) (folded) δ 7.75 (dd, J = 1.1 and 8.2
Hz, 1H), 7.5−7.32 (m, 2H), 7.3 (d, J = 7.7 Hz, 1H), 7.18 (dd, J = 1.2 and
7.0 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.92 (s, br, 1H), 6.78 (d, J = 7.5 Hz,
1H), 6.55 (d, J = 7.5 Hz, 1H), 4.5−4.36 (m, 4H), 4.11 (m, 1H), 4.03
(d, J = 16.9 Hz, 2H), 2.45 (s, 3H), 2.42 (s, 3H), 2.07 (s, 3H), 1.65 (s,
3H), 0.24 (d, J = 6 Hz, 3H), 0.21 (d, J = 6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 154.3, 146.4, 144.3, 141.4, 138.4, 135.7, 132.6, 130.2, 129.8,
129.1, 128.5, 127.9, 127.8, 127.2, 126.6, 125.7, 125.4, 125.1, 124.8, 124.7,
120.1, 106.1, 67.7, 66.5, 54.4, 54.2, 20.0, 19.6, 17.7, 17.0, 16.9, 14.8; IR
2972, 1578, 1474, 1374, 1257, 1219, 1114, 1097, 768, 735; HRMS-ESI
[M + H]+ calcd for C32H35N2O+ 463.2744, found 463.2742.
2-(8-Isopropoxynaphthalen-1-yl)-1,4,7,10-tetramethyl-6,12-
dihydro-5,11-methanodibenzo[b,f ][1,5]diazocine (2b): Yield 24
mg (26%); 1H NMR (300 MHz, CDCl3) (unfolded) δ 7.75 (dd, J = 1.1
and 8.2 Hz, 1H), 7.5−7.3 (m, 3H), 7.03 (dd, J = 1.2 and 7.5 Hz, 1H),
7.03−6.9 (m, 1H), 6.85 (m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 7.5
Hz, 1H), 4.5−4.2 (m, 5H), 4.01 (t, J = 18 Hz, 2H), 2.42 (s, 3H), 2.41 (s,
3H), 2.12 (s, 3H), 1.66 (s, 3H), 0.91 (d, J = 6 Hz, 3H), 0.82 (d, J = 6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 154.3, 146.6, 144.2, 141.4, 138.6,
135.7, 132.8, 130.4, 130.2, 129.2, 128.1, 127.9, 127.2, 126.8, 125.7, 125.4,
125.0, 124.8, 124.6, 120.2, 106.3, 67.9, 66.5, 54.2, 53.7, 20.9, 20.8, 19.6,
17.8, 17.0, 16.8, 14.9; IR 2973, 1579, 1474, 1374, 1258, 1219, 1114,
1097, 768, 731; HRMS-ESI [M + H]+ calcd for C32H35N2O+ 463.2744,
found 463.2744.
2-(8-(Cyclopentyloxy)naphthalen-1-yl)-1,4,7,10-tetramethyl-
6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (3a): Yield
12 mg (12%); 1H NMR (300 MHz, CDCl3) (folded) δ 7.75 (dd, J = 1.1
and 8.2 Hz, 1H), 7.5−7.3 (m, 3H), 7.11 (dd, J = 1.1 and 8.2 Hz, 1H),
7.02−6.97 (m, 1H), 6.84 (s, br, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.58 (d, J =
7.5 Hz, 1H), 4.46 (dd, J = 6.3 and 17 Hz, 2H), 4.33 (m, 2H), 4.2−4.4 (m,
1H), 4.0 (m, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.1 (s, 3H), 1.6 (s, 3H),
1.4−0.6 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 154.7, 146.6, 144.3,
141.5, 138.4, 135.5, 132.6, 130.1, 130.0, 129.0, 128.44, 128.42, 128.3,
127.2, 126.6, 125.7, 125.3, 125.0, 124.9, 120.0, 106.3, 78.3, 66.3, 54.2,
53.9, 31.7, 31.4, 30.9, 23.6, 23.1, 17.8, 17.1, 16.9, 14.7; IR 2943, 1577,
1378, 1257, 1097, 824, 769, 735; HRMS-ESI [M + H]+ calcd for
C34H37N2O+ 489.2900, found 489.2900.
2-(8-(Cyclopentyloxy)naphthalen-1-yl)-1,4,7,10-tetramethyl-
6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (3b): Yield
35 mg (36%); 1H NMR (300 MHz, CDCl3) (unfolded) δ 7.75 (dd, J =
1.1 and 8.2 Hz, 1H), 7.5−7.3 (m, 3H), 7.02−6.97 (m, 2H), 6.84 (s, br,
1H), 6.81 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 4.58 (m, 1H),
4.46 (dd, J = 6.3 and 17 Hz, 2H), 4.33 (m, 2H), 4.01 (t, J = 17 Hz, 2H),
2.42 (s, 3H), 2.40 (s, 3H), 2.12 (s, 3H), 1.65 (s, 3H), 1.74−1.2 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 154.9, 146.6, 144.2, 141.3, 138.5, 135.6,
6.72 (d, J = 7.5 Hz, 1H), 4.5−4.2 (m, 4H), 4.1−3.9 (m, 3H), 2.41
(s, 3H), 2.40 (s, 3H), 2.1 (s, 3H), 1.6 (s, 3H),1.5−0.5 (m, 10H);
13C NMR (75 MHz, CDCl3) δ 154.4, 146.7, 144.3, 141.3, 135.8, 132.9,
130.3, 130.2, 129.3, 128.4, 128.3, 128.2, 128.1, 127.3, 126.8, 125.6, 125.2,
125.0, 124.8, 124.7, 120.2, 106.6, 74.1, 66.5, 54.2, 53.7, 31.0, 30.8, 25.8,
23.8, 23.6, 17.8, 17.1, 16.9, 14.9; IR 2939, 1575, 1505, 1371, 1253, 1069,
822, 727; HRMS-ESI [M + H]+ calcd for C35H39N2O+ 503.3057, found
503.3053.
Cyclopentyl 3-Methyl-2-((2S,5S,11S)-1,4,7,10-tetramethyl-
6,12-dihydro-5,11-methanodibenzo[b,f ][1,5]diazocin-2-yl)-
1
benzoate (5a): Yield 12 mg (13%); H NMR (300 MHz, CDCl3) δ
7.62 (dd, J = 1.2 and 7.5 Hz, 1H), 7.31−7.24 (m, 2H), 6.97 (d, J = 7.5 Hz,
1H), 6.76 (d, J = 7.5 Hz, 1H), 6.69 (s, 1H), 4.81 (m 1H), 4.46 (dd, J = 6
and 17 Hz, 2H), 4.31 (m, 2H), 3.92 (dd, J = 4.5 and 17 Hz, 2H), 2.41 (s,
3H), 2.38 (s, 3H), 2.07 (s, 3H), 1.97 (s, 3H), 1.71 (s, 3H), 1.3−0.5 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 169.0, 146.4, 145.2, 140.5, 137.4,
135.5, 132.7, 132.6, 132.5, 130.2, 129.4, 129.0, 128.5, 127.1, 126.8, 126.4,
126.1, 125.0, 66.2, 54.0, 53.7, 32.0, 31.1, 23.0, 22.9, 20.3, 17.8, 17.06,
16.9, 14.4; IR 2946, 1701, 1436, 1394, 1379, 1335, 1287, 1178, 1096,
+
1066, 979; HRMS-ESI [M + H]+ calcd for C32H37N2O2 481.2850,
found 481.2848.
Cyclopentyl 3-Methyl-2-((2S,5S,11S)-1,4,7,10-tetramethyl-
6,12-dihydro-5,11-methanodibenzo[b,f ][1,5]diazocin-2-yl)-
benzoate (5b): 1H NMR (300 MHz, CDCl3) δ 7.65 (dd, J = 1.2 and 7.5
Hz, 1H), 7.33−7.24 (m, 2H), 7.02 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 7.5
Hz, 1H), 6.70 (s, 1H), 5.07 (m, 1H), 4.46 (dd, J = 8.8 and 16.2 Hz, 2H),
4.23 (q, J = 12 Hz, 2H), 3.9 (d, J = 16.2 Hz, 2H), 2.43 (s, 3H), 2.37 (s,
3H), 2.12 (s, 3H), 1.92 (s, 3H), 1.7 (s, 3H), 1.6−0.8 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 168.9, 146.7, 145.4, 140.5, 137.5, 135.5, 132.9,
132.4, 130.6, 130.4, 129.6, 129.0, 128.3, 127.0, 126.87, 126.8, 125.8,
124.9, 66.1, 54.0, 53.5, 32.3, 32.1, 23.8, 23.7, 20.6, 17.8, 17.0, 16.9, 14.3;
IR 2946, 1702, 1436, 1394, 1354, 1286, 1178, 1097, 1026, 979; HRMS-
ESI [M + H]+ calcd for C32H37N2O2+ 481.2850, found 481.2848.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra are provided for the new balances. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: bbhayana@partners.org.
■
Notes
The authors declare no competing financial interest.
132.9, 130.4, 130.1, 129.1, 128.4, 128.1, 128.0, 127.2, 126.8, 125.7, 125.2,
125.0, 124.6, 124.4, 120.0, 106.0, 78.3, 66.4, 54.2, 53.7, 32.18, 32.14,
24.2, 24.1, 17.8, 17.0, 16.9, 14.8; IR 2942, 1577, 1377, 1257, 1097, 823,
769, 735; HRMS-ESI [M + H]+ calcd for C34H37N2O+ 489.2900, found
489.2900.
ACKNOWLEDGMENTS
■
The author is grateful to Prof. Craig Wilcox for insightful
discussions and helpful comments, and to the Wellman Center
for Photomedicine for providing the opportunity to pursue this
work. The author thanks Prof. Craig Wilcox and the reviewers for
insightful comments and Dr. Haley Ramsey for preperation of
this manuscript.
2-(8-(Cyclohexyloxy)naphthalen-1-yl)-1,4,7,10-tetramethyl-
6,12-dihydro-5,11-methanodibenzo[b,f][1,5]diazocine (4a): Yield
27 mg (27%); 1H NMR (300 MHz, CDCl3) (folded) δ 7.75 (dd, J = 1.1
and 8.2 Hz, 1H), 7.5−7.32 (m, 2H), 7.3 (d, J = 7.7 Hz, 1H), 7.11 (dd, J =
1.2 and 7.0 Hz, 1H), 6.98 (m, br, 1H), 6.89 (s, br, 1H), 6.77 (m, J = 7.5
Hz, 1H), 6.64 (d, J = 7.5 Hz, 1H), 4.48 (d, J = 16.9 Hz, 2H), 4.37 (m,
2H), 4.0 (dd, J = 8.8 and 16.9 Hz, 2H), 3.82 (m, 1H), 2.42 (s, 6H), 2.1 (s,
3H), 1.73 (s, 3H),1.5−0.11(m, 10H); 13C NMR (75 MHz, CDCl3) δ
154.2, 141.7, 138.5, 135.7, 132.8, 132.5, 130.3, 130.2, 130.1, 129.2, 128.4,
128.3, 128.1, 127.3, 126.4, 125.6, 125.3, 125.1, 124.8, 120.2, 106.6, 74.6,
66.2, 54.2, 53.9, 53.6, 30.8, 30.6, 25.5, 23.8, 23.6, 17.8, 17.1, 16.9, 14.9; IR
2932, 1505, 1372, 1263, 1063, 823, 735; HRMS-ESI [M + H]+ calcd for
C35H39N2O+ 503.3057, found 503.3055.
REFERENCES
■
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2-(8-(Cyclohexyloxy)naphthalen-1-yl)-1,4,7,10-tetramethyl-
6,12-dihydro-5,11-methanodibenzo[b,f ][1,5]diazocine (4b):
1
Yield 25 mg (25%); H NMR (300 MHz, CDCl3) (unfolded) δ 7.72
2008, 34, 4031.
(dd, J = 1.1 and 8.2 Hz, 1H), 7.5−7.2 (m, 3H), 7.02 (dd, J = 1.2 and 7.5
Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.86 (s, br, 1H), 6.80 (d, J = 7.5 Hz, 1H),
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Note
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(19) The folding ratios of the equilibrated balances were also in
agreement with their folding ratios observed directly at 100 °C using the
VT NMR technique.
(20) Balances were equilibrated at 80 °C in these solvents. The
equilibration was performed in a sealed tube. See Supporting
Information for more details.
(21) CH−π interaction energies up to 1 kcal/mol have been reported
by Shimizu et al. See: Carroll, W. R.; Zhao, C.; Smith, M. D.; Pellechia, P.
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software (www.copasi.org) which is available for download free of
charge on the Internet.
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