Acceleration of amide bond rotation by encapsulation in the hydrophobic interior of a water-soluble supramolecular assembly

Article abstract of DOI:10.1021/jo800991g

(Chemical Equation Presented) The hydrophobic interior cavity of a self-assembled supramolecular assembly exploits the hydrophobic effect for the encapsulation of tertiary amides. Variable-temperature ¹H NMR experiments reveal that the free energy barrier for rotation around the C-N amide bond is lowered by up to 3.6 kcal/mol upon encapsulation. The hydrophobic cavity of the assembly is able to stabilize the less polar transition state of the amide rotation process. Carbon-13 labeling studies showed that the ¹³C NMR chemical shift of the carbonyl resonance increases with temperature for the encapsulated amides, which suggests that the assembly is able to favor a twisted form of the amide.

Full text of DOI:10.1021/jo800991g

Acceleration of Amide Bond Rotation by Encapsulation in the
Hydrophobic Interior of a Water-Soluble Supramolecular Assembly
Michael D. Pluth, Robert G. Bergman,* and Kenneth N. Raymond*
Department of Chemistry, UniVersity of California, Berkeley, California 94720-1460, and Chemistry
DiVision, Lawrence Berkeley National Laboratory, Berkeley, California, 94720
rbergman@berkeley.edu; raymond@socrates.berkeley.edu
ReceiVed May 7, 2008
The hydrophobic interior cavity of a self-assembled supramolecular assembly exploits the hydrophobic
1
effect for the encapsulation of tertiary amides. Variable-temperature H NMR experiments reveal that
the free energy barrier for rotation around the C-N amide bond is lowered by up to 3.6 kcal/mol upon
encapsulation. The hydrophobic cavity of the assembly is able to stabilize the less polar transition state
of the amide rotation process. Carbon-13 labeling studies showed that the 13C NMR chemical shift of the
carbonyl resonance increases with temperature for the encapsulated amides, which suggests that the
assembly is able to favor a twisted form of the amide.
Introduction
The amide functional group plays an important role in the
structure of proteins and is Nature’s most fundamental con-
necting group.1,2 Although the exact nature of the electronic
structure of the amide bond remains somewhat controversial,3-8
addition of the carbonyl charge separation resonance structure
to the classical resonance structures for the amide account for
most of the characteristics of the amide bond (Figure 1a). In
spite of this controversy, many of the unique properties of
amides, such as the hydrolytic stability and the high rotational
barrier around the amide bond, stem from coplanarity of the
atoms in the amide. Despite the large barrier to rotation around
the amide C-N bond, Nature is able to catalyze the rotation
using peptidylproline cis-trans isomerases (PPIases) such as
cyclophilin and FK-506 binding protein.9,10 Structural studies
have shown that the active site of FKBP contains hydrophobic
FIGURE 1. (a) Resonance structures for the amide bond. (b) Depiction
of the rotational process of an amide bond, which proceeds through a
transition state with increased hydrophobic character.
side chains that are able to stabilize the hydrophobic transition
state for amide bond rotation.11-14 During amide bond rotation,
the nitrogen and oxygen atoms must break conjugation, which
leads to a less polar transition state with respect to the ground-
state structure (Figure 1b). Accordingly, desolvation has been
(1) Fischer, G. Angew. Chem., Int. Ed. 1994, 33, 1415.
(2) Lummis, S. C. R.; Beene, D. L.; Lee, L. W.; Lester, H. A.; Broadhurst,
R. W.; Dougherty, D. A. Nature 2005, 438, 248.
(3) Wiberg, K. B.; Breneman, C. L. J. Am. Chem. Soc. 1992, 114, 831.
(4) Wiberg, K. B.; Laidig, K. E. J. Am. Chem. Soc. 1987, 109, 5935.
(5) Perrin, C. L. J. Am. Chem. Soc. 1991, 113, 2865.
(6) Gatti, C.; Fantucci, P. J. Phys. Chem. 1993, 97, 11677.
(7) Laidig, K. E. J. Am. Chem. Soc. 1992, 114, 7912.
(8) Lauvergnat, D.; Hiberty, P. C. J. Am. Chem. Soc. 1997, 119, 9478.
(9) Fischer, G. Chem. Soc. ReV. 2000, 29, 119.
(11) Kallen, J.; Spitzfaden, C.; Zurini, M. G. M.; Wider, G.; Widmer, H.;
Wuthrich, K.; Walkinshaw, M. D. Nature 1991, 353, 276.
(12) Michnick, S. W.; Rosen, M. K.; Wandless, T. J.; Karplus, M.; Schreiber,
S. L. Science 1991, 252, 836.
(13) Moore, J. M.; Peattie, D. A.; Fitzgibbon, M. J.; Thompson, J. A. Nature
1991, 351, 248.
(10) Mohanty, J.; Bhasikuttan, A. C.; Nau, W. M.; Pal, H. J. Phys. Chem. B
2006, 110, 5132.
(14) Van Duyne, G. D.; Standaert, R. F.; Karplus, P. A.; Schreiber, S. L.;
Clardy, J. Science 1991, 252, 839.
7132 J. Org. Chem. 2008, 73, 7132–7136
10.1021/jo800991g CCC: $40.75 2008 American Chemical Society
Published on Web 08/08/2008

Amide Bond Rotation in a Supramolecular Assembly
FIGURE 2. (Left) Schematic representation of 1 with only one ligand
shown for clarity. (Right) Space-filling model of 1.
1
FIGURE 3. Variable-temperature H NMR spectra of [2 ⊂ 1]12-
.
implicated as a significant contributor to the activity of PPIases
and their ability to reduce the activation barrier for peptide bond
rotation by up to 8 kcal/mol.15
aspects of the interior of 1 to affect chemical catalysis. The
size constraints of the cavity have been used to preorganize
substrates into a reactive conformation for the [3,3] sigmatropic
aza-Cope rearrangement,26,27 and the preference for monoca-
tionic guests has facilitated the acid-catalyzed hydrolysis of
orthoformates and acetals in basic solution.28-30
Synthetic host molecules have proved useful in favoring
reactivity that is affected by desolvation. For example, both
natural cyclodextrins and a variety of synthetic supramolecular
assemblies are able to encapsulate Diels-Alder reactants and
increase the rate of the reaction. Similarly, the rotational
behavior of amides has been investigated in synthetic host-guest
systems by both the Cram and Rebek groups.16,17 In both cases,
the amide rotational barrier was altered (e1.5 kcal/mol), either
increasing or decreasing, depending on the substrate. This
suggests that while the hydrophobicity of the transition state
may be favored upon encapsulation, other forces are present
that impede rotation and are of similar magnitude as the effects
of hydrophobicity alone. Herein we report the use of a water-
soluble supramolecular assembly to greatly and exclusively
reduce the barrier for amide bond rotation of encapsulated
substrates.
Recent work from our laboratory has shown that the
hydrophobic effect drives encapsulation of neutral guests in 1.31
This prompted our search for other transformations of neutral
substrates that could be accelerated by 1. With this in mind,
we hoped that the hydrophobic cavity of 1 could stabilize the
hydrophobic transition state for amide bond rotation. In order
to test this hypothesis, N,N-diisopropylbenzamide (2) was
encapsulated in 1 and its dynamic behavior was probed with
1
1
variable-temperature H NMR studies. Coalescence of the H
NMR resonances corresponding to encapsulated 2 was observed,
and the coalescence temperature was lower than for 2 in D2O
alone (Figure 3). Measurement of the coalescence temperature
(Tc) and the difference in frequency of the coalescing peaks
(∆V) enabled determination of the activation barrier for the bond
rotation process.32
Results and Discussion
The tetrahedral supramolecular assembly [Ga4L6]12- (1, L )
N,N′-bis(2,3-dihydroxybenzoyl)-1,5-diaminonaphthalene) (Fig-
ure 2) has been investigated by the Raymond group over the
past decade.18-22 The 12- overall charge of 1 imparts water
solubility, and the interior of 1 provides a hydrophobic cavity
isolated from bulk solution. The tris-bidentate coordination at
the metal vertices makes each vertex a stereocenter, and the
strong mechanical coupling of the ligands transfers the chirality
of one metal vertex to the others forming the homochiral ∆∆∆∆
or ΛΛΛΛ isomers of the assembly. The hydrophobic interior
has been exploited to encapsulate a variety of hydrophobic
guests and has been used to stabilize species otherwise unstable
in water, such as phosphine-acetone adducts, iminium cations,
and tropylium.23-25 We have previously exploited different
The range of amides encapsulated in 1 was expanded by
exposing suitable substrates to the assembly (Figure 4). Since
the coalescence temperature was different for the amides in free
solution and encapsulated in 1, the assumption that ∆Sq ≈ 0 is
necessary for comparison of the free energies and is validated
by the almost entirely enthalpic barrier for amide bond
rotation.33,34 In all cases, a reduction in the barrier for amide
bond rotation was observed upon encapsulation in 1 when
compared to the free energy of rotation in D2O solution. The
difference upon encapsulation was greatest for N,N-dipropylni-
(24) Dong, V. M.; Fiedler, D.; Carl, B.; Bergman, R. G.; Raymond, K. N.
J. Am. Chem. Soc. 2006, 128, 14464.
(25) Ziegler, M.; Brumaghim, J. L.; Raymond, K. N. Angew. Chem., Int.
Ed. 2000, 39, 4119.
(26) Fiedler, D.; Bergman, R. G.; Raymond, K. N. Angew. Chem., Int. Ed.
2004, 43, 6748–6751.
(27) Davis, A. V.; Fiedler, D.; Seeber, G.; Zahl, A.; van Eldik, R.; Raymond,
K. N. J. Am. Chem. Soc. 2006, 128, 1324.
(28) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. Science 2007, 316, 85.
(29) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. J. Am. Chem. Soc. 2007,
129, 11459.
(15) Kofron, J. L.; Kuzmic, P.; Kishore, V.; Colon-Bonilla, E.; Rich, D. H.
Biochemistry 1991, 30, 6127.
(16) Salvio, R.; Moisan, L.; Ajami, D.; Rebek, J., Jr Eur. J. Org. Chem.
2007, 16, 2722.
(17) Sherman, J. C.; Knobler, C. B.; Cram, D. J. J. Am. Chem. Soc. 1991,
113, 2194.
(18) Caulder, D. L.; Powers, R. E.; Parac, T. N.; Raymond, K. N. Angew.
Chem., Int. Ed. 1998, 37, 1840.
(19) Caulder, D. L.; Raymond, K. N. Acc. Chem. Res. 1999, 32, 975.
(20) Davis, A. V.; Fiedler, D.; Seeber, G.; Zahl, A.; van Eldik, R.; Raymond,
K. N. J. Am. Chem. Soc. 2006, 128, 1324.
(21) Davis, A. V.; Raymond, K. N. J. Am. Chem. Soc. 2005, 127, 7912.
(22) Fiedler, D.; Leung, D. H.; Bergman, R. G.; Raymond, K. N. Acc. Chem.
Res. 2005, 38, 349.
(30) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. Angew. Chem., Int. Ed.
2007, 119, 8741.
(31) Biros, S. M.; Bergman, R. G.; Raymond, K. N. J. Am. Chem. Soc. 2007,
129, 12094.
(32) Allerhand, A.; Gutowsky, H. S.; Jonas, J.; Meinzer, R. A. J. Am. Chem.
Soc. 1966, 88, 3185.
(33) Drakenberg, T.; Dahlqvist, K. I.; Forsen, S. J. Phys. Chem. 1972, 76,
2178.
(23) Brumaghim, J. L.; Michels, M.; Pagliero, D.; Raymond, K. N. Eur. J.
Org. Chem. 2004, 24, 5115.
(34) Eberhardt, E. S.; Loh, S. N.; Hinck, A. P.; Raines, R. T. J. Am. Chem.
Soc. 1992, 114, 5437.
J. Org. Chem. Vol. 73, No. 18, 2008 7133

Pluth et al.
FIGURE 6. Approximation of the potential energy surface for amide
bond rotation as a function of the twist angle φ.
FIGURE 4. Scope of amides encapsulated in 1.
TABLE 1. Activation Barriers for Amide Bond Rotation in D2O,
in 1, and in Toluenea
b
guest
∆Gq (D2O)
∆Gq (in 1)
∆Gq (toluene)
∆∆Gq
2
3
4
5
6
7
8
9
16.7
16.4
17.3
16.0
17.5
17.5
17.9
16.5
17.6
14.7
14.2
15.5
13.8
14.7
14.2
14.3
14.3
16.7
12.8
13.0
13.9
12.6
14.0
14.3
14.2
13.2
14.7
2.0
2.2
1.8
2.2
2.8
3.3
3.6
2.3
1.9
FIGURE 7. Comparison of the energy well for non-twisted (a) and
10
twisted (b) amides.
b
a In kcal/mol with uncertainty of
( )
0.2 kcal/mol. ∆∆Gq
∆Gq(D2O) - ∆Gq (in 1).
barrier reduction in 1, have the most flexibility and can attain
conformations in 1 to avoid the unfavorable steric interactions.
This suggests that although the interior of 1 hampers the
rotational freedom of the encapsulated amide, it is the hydro-
phobicity of the cavity that dominates the reactivity.
To further probe the origin of the acceleration, carbon-13
labeling experiments were pursued. A number of reports in the
literature have studied the relationship between the twist angle
of amides and the 13C{1H} NMR shifts in solution.35,36 In
general, the 13C{1H} chemical shift increases as a function of
the amide twist angle. We verified these conclusions compu-
tationally for the model compound 2 using DFT NMR tensor
calculations using Gaussian 03 (see Supporting Information).37
For experimental measurements, 13C-labeled 2 (13C-2) was
prepared by treating R-13C-benzoylchloride with an excess of
diisopropylamine.
Variable-temperature 13C NMR experiments in both D2O and
d8-toluene revealed that the 13C{1H} chemical shift was unaf-
fected by temperature. This suggests that although bond rotation
was occurring, the ground-state structure remained unchanged.
However, a sizable shift of over 1 ppm was observed for [13C-
2 ⊂ 1]12- from 277 to 360 K (Figure 5). During the experiment,
the 13C NMR shifts of the resonances corresponding to excess
13C-2 in solution did not change, thereby suggesting that guest
exchange was not responsible for the change in 13C chemical
shift. When compared to the theoretical studies on the effects
of amide twist angle on the 13C NMR shifts, these labeling
studies suggest that encapsulation in 1 may perturb the potential
energy surface for the bond rotation process and stabilize a more
hydrophobic twisted form of the encapsulated amide.
FIGURE 5. Observed 13C{1H} chemical shifts of 2 in D2O both with
and without [2 ⊂ 1]12-, in toluene, and encapsulated in 1.
cotinamide (8), in which case the barrier for bond rotation was
reduced by 3.6 kcal/mol (Table 1), corresponding to a rate
acceleration of bond rotation by a factor of ∼450.
To investigate the maximum difference in rotation barrier
based on hydrophobic effect alone, toluene was chosen as a
solvent that should be similar to the interior of 1. In all cases,
the rotational barrier for amides in toluene was lower than in
D2O alone. Interestingly, the rotational barrier in toluene was
less than or equal to that observed in 1 and provides a suitable
experimental temperature range. If the acceleration of the bond
rotation in 1 were solely due to the hydrophobic interior of 1,
then the rotational barrier would be expected to be identical
for amides in toluene. However, this is not the case. The
rotational barriers are generally lower in toluene which suggests
that unfavorable steric interactions in 1 are likely present which
attenuate the magnitude of the acceleration. Similarly, the alkyl
groups on amides 7 and 8, the amides with the greatest rotational
For example, if the potential energy surface for amide bond
rotation by a dihedral angle of φ is approximated as a sine
function with an activation barrier for rotation, A (Figure 6),
(35) Yamada, S. Angew. Chem., Int. Ed. 1995, 24, 1113.
(36) Yamada, S. J. Org. Chem. 1996, 61, 941.
(37) Frisch, M. J. et al. Gaussian 03, ReVision D.01, Gaussian, Inc.:
Wallingford, CT, 2004.
7134 J. Org. Chem. Vol. 73, No. 18, 2008

Amide Bond Rotation in a Supramolecular Assembly
energies for rotation were determined using the coalescence method
by determining the coalescence temperature (Tc) and chemical shift
difference at the slow exchange limit (∆υ) from eq 4. In all cases,
when multiple decoalescing peaks could be followed, the activation
barriers determined from the different peaks were identical. The
uncertainty in ∆Gqinv was calculated using differential error analysis
by eq 5.
then the energy of any point on the potential energy surface for
bond rotation is proportional to φ by the relationship shown in
eq 1. Since amides are generally planar, the lowest energy
structure has a twist angle of φ ≈ 0.
E ) A sin2 ꢀ
(1)
Differentiating the expression in eq 1 with respect to φ allows
for determination of the maxima and minima of the potential
energy curve for amide bond rotation (eq 2). Further differentia-
tion provides an expression for the force constant, k, corre-
sponding to the dihedral rotational process around the C-N
bond of the amide (eq 3).
RTc
∆Gq ) RTc ln
(4)
(
)
kcNAh
∂ ∆Gq
∂ ∆Gq
2
2
(
)
(
)
inv
inv
σ ∆Gq
)
σ ∆υ +
σ2 T
( )
c
(5)
2
(
)
(
)
(
)
inv
(
)
(
)
∂ δυ
∂ T
( )
c
ꢀ
∂E
∂ꢀ
[13C-N,N-Diisopropylbenzamide] (13C-2). To a 10 mL round-
bottom flask were added 13C-benzoic acid (241 mg, 1.96 mmol),
thionyl chloride (0.75 mL, 10.2 mmol), and DMF (15 µL). The
reaction mixture was allowed to stir for 30 min, at which point it
was heated to 50 °C for 5 min and then cooled to room temperature.
The thionyl chloride was removed carefully under vacuum, at which
point 25 mL of CH2Cl2 was added to the resultant oil. Diisopro-
pylamine (2.2 mL, 16 mmol) was added with a syringe, and the
reaction mixture was stirred for an additional 30 min. The reaction
mixture was then washed with 1 N HCl (2 × 10 mL), 1 N NaOH
(2 × 10 mL), and brine (1 × 10 mL) and dried over MgSO4, and
the solvent was removed under vacuum to yield a white powder.
The crude product was dissolved in a minimal amount of boiling
hexane (∼3 mL) and filtered through a preheated glass wool plug.
Slow cooling the filtrate to -70 °C yielded a white microcrystalline
product which was dried under vacuum to give the title compound
(285 mg, 71% yield). 1H NMR (500 MHz, CDCl3): δ 7.38 (m, 3H,
3 × CH), 7.32 (m, 2H, 2 × CH), 3.84 (bs, 1H, CH), 3.54 (bs, 1H,
CH), 1.59 (bs, 6H, 2 × CH3), 1.16 (bs, 6H, 2 × CH3). 13C{1H}
NMR (125 MHz, CDCl3): δ 171.5 (13C), 139.4 (d, J ) 65 Hz),
129.0, 128,8 (d, J ) 4.3 Hz), 126.0 (d, J ) 1.4 Hz), 51.1 (bs, CH),
46.1 (bs, CH), 21.1 HRMS: obs (calc): 207.157870 (207.157844).
IR [neat, νmax (cm-1)]: 2992 (w), 2967 (m), 2931 (w), 1601 (w),
1584 (s, VCO), 1562 (w), 1471 (w), 1436 (s), 1361 (m), 1323 (s),
1211 (m), 1186 (w), 1156 (m), 1134 (m), 1095 (w), 1039 (w), 1026
(m), 780 (m), 733 (w), 706 (m). Mp 70-71 °C.
) 2A sin ꢀ cos ꢀ ) A sin 2ꢀ
(2)
(3)
∂2E
) 2A cos 2ꢀ ) k
∂2ꢀ
Thus, in the planar form of an amide (φ ≈ 0) the energy
surface for rotation around the C-N bond is symmetric and
the force constant for dihedral rotation only depends on the
activation barrier (k ) 2A). However, if the lowest energy (E
) 0) conformation of the amide is twisted rather than planar,
(φ * 0), the potential energy surface for dihedral rotation is
more broad and is asymmetric (k ) 2A cos 2φ) (Figure 7). The
broader potential energy surface for dihedral rotation would
account for and is consistent with the observed increase in
13C{1H} shift of the amide in 1. Stabilization of a twisted form
of encapsulated amides in 1 would result in destabilization of
the ground state of the amide more than the transition state;
this would consequently result in a lower rotational barrier for
the amide encapsulation in 1.
Conclusion
In summary, we have exploited the hydrophobic interior of
a self-assembled supramolecular assembly to greatly accelerate
the rotation of encapsulated amides. Variable-temperature 13C
NMR labeling experiments suggest that the potential energy
surface of amide rotation inside of the assembly is considerably
different from that in free solution and that ground-state
destabilization may contribute to the observed acceleration.
[N,N-Diisopropyl-d5-benzamide] (3). To a 10 mL round-bottom
flask were added d5-benzoic acid (323 mg, 2.54 mmol), thionyl
chloride (2.0 mL, 27.4 mmol), and DMF (15 µL). The reaction
mixture was allowed to stir for 30 min, at which point it was heated
to 50 °C for 5 min and then cooled to room temperature. The thionyl
chloride was removed carefully under vacuum, at which point 25
mL of CH2Cl2 was added to the resultant oil. Diisopropylamine
(3.5 mL, 25.0 mmol) was added with a syringe, and the reaction
mixture was stirred for an additional 30 min. The reaction mixture
was then washed with 1 N HCl (2 × 10 mL), 1 N NaOH (2 × 10
mL), and brine (1 × 10 mL) and dried over MgSO4, and the solvent
was removed under vacuum to yield a white powder. The crude
product was dissolved in a minimal amount of boiling hexane and
filtered through a preheated glass wool plug. Cooling the filtrate to
-70 °C yielded a white microcrystalline product which was dried
under vacuum to give the title compound (408 mg, 76% yield). 1H
NMR (500 MHz, (CD3)2CO): δ 3.70 (bs, 2H, 2 × CH), 1.32 (bs,
12H, 4 × CH3). 2H NMR (76.7 MHz, (CD3)2CO): δ 7.39 (bs, 3H,
3 × CH), 7.29 (bs, 2H, 2 × CH). 13C{1H} NMR (125 MHz,
(CD3)2CO): δ 170.0, 139.4, 127.8 (t, J ) 24.7 Hz), 127.7 (t, J )
24.6 Hz), 125.0 (t, J ) 24.6 Hz), 45.2, 19.9. HRMS: obs (calc):
211.185840 (211.185873). IR [neat, νmax (cm-1)]: 2992 (w), 2967
(m), 2931 (w), 2872 (w), 1621 (s), 1567 (w), 1468 (w), 1449 (m),
1316 (s), 1222 (w), 1157 (w), 1135 (w), 1077 (w), 1033 (m), 847
(m), 813 (w), 777 (w), 748 (w), 677 (w). Mp 69-70 °C.
Experimental Section
General Procedures. All NMR spectra were obtained using a
Bruker AV-500 MHz spectrometer at the indicated frequencies.
Chemical shifts are reported as parts per million (δ) and referenced
1
to residual acetone (for H) and or a capillary of dioxane (13C).
Amides were prepared by addition of an excess of the corresponding
secondary amine to the desired acid chloride. All amide products
were purified by either distillation or recrystallization from hot
hexanes. The following abbreviations are used in describing NMR
couplings: (s) singlet, (d) doublet, (t) triplet, (q) quartet, b (broad),
m (multiplet). The temperature of all variable-temperature NMR
experiments was calibrated with methanol or ethylene glycol
standards.38 Infrared (IR) spectra were recorded on a Nicolet 380
FT-IR spectrometer.
Determination of ∆Gqinv using the Coalescence Temperature
Method. Analysis of coalescence data using line shape analysis was
not possible as a result of both encapsulation and guest exchange
affecting the peak width of encapsulated substrates. Activation
General Procedure for Amide Encapsulation. In an N2 glovebox,
15 mg of K12[Ga4L6] was added to an NMR tube, at which point
0.5 mL of D2O was added. An excess of the amide (10 mg or 10
µL) was added by syringe or as a solid, and the NMR tube was
(38) Amman, C.; Meier, P.; Merbach, A. E. J. Magn. Reson. A 1982, 46,
319.
J. Org. Chem. Vol. 73, No. 18, 2008 7135

Pluth et al.
shaken for 30 s. For host-guest complexes, the encapsulated guest
resonances are generally shifted upfield by 2-3 ppm, which is
consistent with encapsulation. Depending on the chemical shift of
aromatic guests, some of the guest resonances overlap with the
assembly resonances.
J ) 8.0 Hz, 12H, aryl). Guest: 2 aryl H overlapping with host,
3.84 (s, 2H, 2 × CH), -0.02 (bs, 2H, 2 × CH), -1.53 (bs, 12H,
4 × CH3).
1
[N,N-Diethylnicotinamide ⊂ Ga4L6]12- ([7 ⊂ 1]12-). H NMR
(500 MHz, D2O, 278 K): δ 8.11 (bs, 12H, aryl), 7.28 (bs, 12H,
aryl), 6.52 (bs, 12H, aryl), 6.35 (d, J ) 7.4 Hz, 12H, aryl), 6.21
(bs, 12H, aryl), 6.14 (bs, 12H, aryl). Guest: 4.78 (s, 1H, CH), (other
CH overlapping with cluster) -0.31 (s, 2H, CH2), -0.46 (s, 2H,
CH2), -1.57 (s, 3H, CH3), -1.68 (s, 3H, CH3). 1H NMR (500 MHz,
D2O, 313 K): δ 8.14 (d, J ) 7.6 Hz, 12H, aryl), 7.21 (bs, 12H,
aryl), 6.55 (t, J ) 8.0 Hz, 12H, aryl), 6.31 (d, J ) 7.4 Hz, 12H,
aryl), 6.19 (t, J ) 7.6 Hz, 12H, aryl), 6.12 (bs, 12H, aryl). Guest:
4.73 (s, 1H, CH), (other CH overlapping with cluster) -0.31 (bs,
4H, 2 × CH2), -1.62 (bs, 6H, 2 × CH3).
[N,N-Diisopropylbenzamide ⊂ Ga4L6]12- ([2 ⊂ 1]12-). 1H NMR
(500 MHz, D2O, 300 K): δ 7.77 (d, J ) 7.5 Hz, 12H, aryl), 7.65
(t, J ) 8.0 Hz, 12H, aryl), 7.21 (d, J ) 8.0 Hz, 12H, aryl), 6.69 (t,
J ) 8.0 Hz, 12H, aryl), 6.65 (d, J ) 8.0 Hz, 12H, aryl), 6.49 (t, J
) 7.6 Hz, 12H, aryl). Guest: 5.99 (t, J ) 7.0 Hz, 1H, CH), 5.50 (t,
J ) 7.0 Hz, 2H, 2 × CH), 3.58 (bs, 2H, 2 × CH), 0.28 (s, 1H,
CH), -0.06 (s, 1H, CH), -1.00 (s, 3H, CH3), -1.23 (s, 3H, CH3),
-1.47 (s, 3H, CH3), -1.80 (s, 3H, CH3). 1H NMR (500 MHz, D2O,
330 K): δ 7.83 (d, J ) 7.5 Hz, 12H, aryl), 7.59 (t, J ) 8.0 Hz,
12H, aryl), 7.22 (d, J ) 8.0 Hz, 12H, aryl), 6.87 (t, J ) 8.0 Hz,
12H, aryl), 6.65 (d, J ) 7.6 Hz, 12H, aryl), 6.50 (t, J ) 7.6 Hz,
12H, aryl). Guest: 5.82 (bs, 1H, CH), 5.65 (bs, 2H, 2 × CH), 3.35
(bs, 2H, 2 × CH), 0.01 (bs, 2H, 2 × CH), -1.35 (bs, 12H, 4 ×
CH3).
[N,N-Dipropylnicotinamide ⊂ Ga4L6]12- ([8 ⊂ 1]12-). 1H NMR
(500 MHz, D2O, 277 K): δ 7.34 (bs, 12H, aryl), 7.13 (d, J ) 8.0
Hz, 12H, aryl), 6.84 (bs, 12H, aryl), 6.61 (d, J ) 8.0 Hz, 12H,
aryl), 6.42 (bs, 12H, aryl), 6.18 (bs, 12H, aryl). Guest: 5.38 (s, 1H,
CH), 5.22 (s, 1H, CH), 4.57 (s, 1H, CH), (other 2 CH overlapping
with cluster), 0.08 (s, 2H, CH2), -0.48 (s, 2H, CH2), -0.81 (s,
2H, CH2), -1.36 (s, 2H, CH2), -1.41 (s, 3H, CH3), -1.74 (s, 3H,
[N,N-Diisopropyl-d5-benzamide ⊂ Ga4L6]12- [3 ⊂ 1]12-. 1H NMR
(500 MHz, D2O, 290 K): δ 7.77 (d, J ) 7.6 Hz, 12H, aryl), 7.72
(t, J ) 8.0 Hz, 12H, aryl), 7.24 (d, J ) 8.0 Hz, 12H, aryl), 6.93 (t,
J ) 8.0 Hz, 12H, aryl), 6.72 (d, J ) 8.0 Hz, 12H, aryl), 6.55 (t, J
) 7.6 Hz, 12H, aryl). Guest: 0.41 (s, 1H, CH), -0.17 (s, 1H, CH),
-1.01 (s, 3H, CH3), -1.17 (s, 3H, CH3), -1.27 (s, 3H, CH3), -1.75
1
CH3). H NMR (500 MHz, D2O, 319 K): δ 7.66 (d, J ) 8.0 Hz,
12H, aryl), 7.37 (d, J ) 8.0 Hz, 12H, aryl), 7.14 (bs, 12H, aryl),
6.86 (d, J ) 8.0 Hz, 12H, aryl), 6.60 (bs, 12H, aryl), 6.42 (t, J )
7.6 Hz, 12H, aryl). Guest: 5.61 (s, 1H, CH), 5.58 (s, 1H, CH),
4.81 (s, 1H, CH), (other 2 CH overlapping with cluster), -0.10 (s,
4H, 2x CH2), -0.90 (s, 4H, 2 × CH2), -1.61 (s, 4H, 2 × CH2).
[N,N-Diisopropylnicotinamide ⊂ Ga4L6]12- ([9 ⊂ 1]12-). 1H NMR
(500 MHz, D2O, 277 K): δ 7.78 (bs, 12H, aryl), 7.43 (bs, 12H,
aryl), 7.17 (bs, 12H, aryl), 6.83 (bs, 12H, aryl), 6.73 (bs, 12H, aryl),
6.57 (bs, 12H, aryl). Guest: 5.07 (s, 1H, CH), 4.55 (s, 1H, CH),
3.20 - 3.26 (bs, 2H, 2 CH), 0.45 (s, 1H, CH), -0.01 (s, 1H, CH),
-0.55 (s, 3H, CH3), -0.81 (s, 3H, CH3), -1.72 (s, 3H, CH3), -1.95
1
(s, 3H, CH3). H NMR (500 MHz, D2O, 325 K): δ 7.87 (d, J )
7.5 Hz, 12H, aryl), 7.52 (t, J ) 8.0 Hz, 12H, aryl), 7.25 (d, J )
8.0 Hz, 12H, aryl), 6.87 (t, J ) 8.0 Hz, 12H, aryl), 6.63 (d, J )
7.4 Hz, 12H, aryl), 6.53 (t, J ) 7.6 Hz, 12H, aryl). Guest: 0.04
(bs, 2H, 2 × CH), -1.38 (bs, 12H, 4 × CH3).
1
[1-Benzoylpiperidine ⊂ Ga4L6]12- ([4 ⊂ 1]12-). H NMR (500
MHz, D2O, 296 K): δ 7.68 (bs, 24H, aryl), 7.16 (d, J ) 7.6 Hz,
12H, aryl), 6.89 (bs, 12H, aryl), 6.65 (d, J ) 7.4 Hz, 12H, aryl),
6.47 (t, J ) 7.6 Hz, 12H, aryl). Guest: 5.98 (s, 1H, CH), 5.05 (s,
2H, 2 × CH), 4.30 (s, 2H, 2 × CH), -1.03 (s, 2H, CH2), -1.14
(s, 2H, CH2), -1.50 (s, 2H, CH2), -1.92 (s, 2H, CH2), -1.97 (s,
1
(s, 3H, CH3). H NMR (500 MHz, D2O, 322 K): δ 7.89 (d, J )
7.5 Hz, 12H, aryl), 7.48 (d, J ) 8.0 Hz, 12H, aryl), 7.31 (t, J )
7.5 Hz, 12H, aryl), 7.08 (t, J ) 7.5 Hz, 12H, aryl), 6.73 (d, J )
7.5 Hz, 12H, aryl), 6.35 (t, J ) 7.5 Hz, 12H, aryl). Guest: 5.15 (s,
1H, CH), 4.59 (s, 1H, CH), 3.47 (s, 1H, CH), 3.40 (s, 1H, CH),
-0.23 (bs, 2H, 2 × CH), -1.27 (s, 12H, 4 × CH3).
1
2H, CH2). H NMR (500 MHz, D2O, 357 K): δ 7.78 (bs, 12H,
aryl), 7.62 (bs, 12H, aryl), 7.15 (bs, 12H, aryl), 6.90 (bs, 12H, aryl),
6.65 (bs, 12H, aryl), 6.46 (bs, 12H, aryl). Guest: 5,75 (s, 1H, CH),
5.19 (s, 2H, 2 × CH), 4.43 (s, 2H, 2 × CH), -0.90 (bs, 4H, 2 ×
CH2), -1.52 (bs, 2H, CH2), -1.85 (bs, 4H, 2 × CH2).
[N,N-Diisopropylpivalamide ⊂ Ga4L6]12- ([10 ⊂ 1]12-). 1H NMR
(500 MHz, D2O, 277 K): δ 7.98 (bs, 12H, aryl), 7.69 (bs, 12H,
aryl), 7.29 (bs, 12H, aryl), 6.85 (bs, 12H, aryl), 6.65 (bs, 12H, aryl),
6.54 (bs, 12H, aryl). Guest: 0.50 (s, 1H, CH), -0.52 (s, 1H, CH),
-1.36 (d, J ) 7.0 Hz, 3H, CH3), -1.46 (d, J ) 7.0 Hz, 3H, CH3),
-1.59 (d, J ) 7.0 Hz, 3H, CH3), -1.62 (d, J ) 7.0 Hz, 3H, CH3),
[N,N-Diisopropyl-p-fluorobenzamide ⊂ Ga4L6]12- ([5 ⊂ 1]12-).
1H NMR (500 MHz, D2O, 277 K): δ 7.17 (bs, 12H, aryl), 7.01
(bs, 12H, aryl), 6.78 (d, J ) 7.5 Hz, 12H, aryl), 6.67 (d, J ) 7.5
Hz, 12H, aryl), 6.57 (t, J ) 8.0 Hz, 12H, aryl), 6.50 (bs, 12H,
aryl). Guest: 5.05 (bs, 2H, 2 CH), 3.55 (s, 2H, 2 CH), 0.53 (bs,
1H, CH), -0.03 (bs, 1H, CH), -0.88 (bs, 3H, CH3), -1.18 (bs,
1
-1.75 (s, 9H, 3 × CH3). H NMR (500 MHz, D2O, 346 K): δ
7.94 (bs, 12H, aryl), 7.58 (d, J ) 7.6 Hz, 12H, aryl), 7.26 (d, J )
8.0 Hz, 12H, aryl), 6.65 (bs, 12H, aryl), (other two cluster
resonances overlapping with exterior guest), Guest: -0.04 (s, 2H,
2 × CH), -1.44 (bs, 12H, 4 × CH3), -1.76 (s, 9H, 3 × CH3).
1
3H, CH3), -1.36 (bs, 3H, CH3), -2.00 (bs, 3H, CH3). H NMR
(500 MHz, D2O, 332 K): δ 7.87 (d, J ) 7.5 Hz, 12H, aryl), 7.66
(d, J ) 8.0 Hz, 12H, aryl), 7.18 (d, J ) 8.0 Hz, 12H, aryl), 6.89 (t,
J ) 8.0 Hz, 12H, aryl), 6.62 (d, J ) 8.0 Hz, 12H, aryl), 6.49 (t, J
) 8.0 Hz, 12H, aryl). Guest: 5.36 (bs, 2H, 2 × CH), 3.79 (bs, 2H,
2 × CH), 0.04 (bs, 2H, 2 × CH), -1.30 (bs, 12H, 4 × CH3).
Acknowledgment. This work was supported by the Director,
Office of Science, Office of Basic Energy Sciences, and the
Division of Chemical Sciences, Geosciences, and Biosciences
of the U.S. Department of Energy at LBNL under Contract No.
DE-AC02-05CH11231 and an NSF predoctoral fellowship to
M.D.P.
1
[N,N-Diisopropylisonicotinamide ⊂ Ga4L6]12- ([6 ⊂ 1]12-). H
NMR (500 MHz, D2O, 277 K): δ 7.48 (d, J ) 7.5 Hz, 12H, aryl),
7.35 (d, J ) 8.0 Hz, 12H, aryl), 6.99 (d, J ) 7.4 Hz, 12H, aryl),
6.38 (t, J ) 8.0 Hz, 12H, aryl), 6.40 (d, J ) 7.5 Hz, 12H, aryl),
6.22 (t, J ) 7.5 Hz, 12H, aryl). Guest: 2 aryl H overlapping with
host, 3.23 (s, 2H, 2 CH), 0.33 (s, 1H, CH), -0.09 (s, 1H, CH),
-1.04 (s, 3H, CH3), -1.18 (s, 3H, CH3), -1.44 (s, 3H, CH3), -1.99
Supporting Information Available: Computation details,
NMR spectra, and complete ref 37. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
(s, 3H, CH3). H NMR (500 MHz, D2O, 340 K): δ 7.76 (d, J )
8.0 Hz, 12H, aryl), 7.68 (d, J ) 7.6 Hz, 12H, aryl), 7.17 (bs, 12H,
aryl), 6.90 (d, J ) 7.5 Hz, 12H, aryl), 6.60 (bs, 12H, aryl), 6.43 (t,
JO800991G
7136 J. Org. Chem. Vol. 73, No. 18, 2008