Cavitands with introverted functionality stabilize tetrahedral intermediates

Article abstract of DOI:10.1021/ja0756366

The synthesis and characterization of two deepened cavitand hosts with introverted functionality - f unctional groups directed into the cavity - is described. Two functions can be introverted, alcohol and aldehyde, and they show the formation of hemiacetals and hemiketals on binding small guests with complementary functional groups. The structures of the bound hemiacetals are determined by 1D and 2D NMR studies. The arrangements of the guests in the cavitands enhance the equilibrium constants of carbonyl additions, K/K _ctrl, between 13- and 10⁵-fold, compared to their counterparts in solution. The stabilization of the addition products is due to the prior complexation of the guests and the organized solvation provided to the tetrahedral intermediates by a network of secondary amides at the cavitand rim.

Full text of DOI:10.1021/ja0756366

Published on Web 11/16/2007
Cavitands with Introverted Functionality Stabilize Tetrahedral
Intermediates
Richard J. Hooley, Per Restorp, Tetsuo Iwasawa, and Julius Rebek, Jr.*
Contribution from The Skaggs Institute for Chemical Biology and Department of Chemistry, The
Scripps Research Institute, MB-26, 10550 North Torrey Pines Road, La Jolla, California 92037
Received July 27, 2007; E-mail: jrebek@scripps.edu
Abstract: The synthesis and characterization of two deepened cavitand hosts with introverted functionalitys
functional groups directed into the cavitysis described. Two functions can be introverted, alcohol
and aldehyde, and they show the formation of hemiacetals and hemiketals on binding small guests
with complementary functional groups. The structures of the bound hemiacetals are determined by 1D
and 2D NMR studies. The arrangements of the guests in the cavitands enhance the equilibrium con-
stants of carbonyl additions, K/Kctrl, between 13- and 105-fold, compared to their counterparts in solution.
The stabilization of the addition products is due to the prior complexation of the guests and the organized
solvation provided to the tetrahedral intermediates by a network of secondary amides at the cavitand
rim.
Introduction
Reactive intermediates have been stabilized by isolation in
covalent carcerands1 and even reversibly formed capsules.2 In
the former, the intermediates are formed irreversibly from
precursors in situ,3 while in the latter the products of unfavorable
chemical equilibria are amplified by surrounding them in a
stabilizing environment. For example, iminium ions are readily
observed in capsules that bear multiple negative charges,4 and
labile silanols are protected from hydrolysis in metal/ligand
capsules.5 The covalent participation of host with guest is under-
represented, largely due to the difficulty of functionalizing
concave molecular surfaces.6 In a recent departure, we intro-
duced the cavitand 1 (Figure 1) and showed its “introverted”
aldehyde stabilizes intermediate hemiaminals with amines that
are accommodated in the cavity.7 Here we apply it and the
derived alcohol 2 to the stabilization and amplification of
hemiacetals.
(1) (a) Cram, D. J. Container Molecules and Their Guests; Royal Society of
Chemistry: Cambridge, UK, 1997. (b) Roach, P.; Warmuth, R. Angew.
Chem., Int. Ed. 2003, 42, 3039-3042. (c) Warmuth, R.; Marvel, M. A.
Angew. Chem., Int. Ed. 2000, 39, 1117-1119.
(2) (a) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Angew. Chem., Int.
Ed. 2002, 41, 1488-1508. (b) Fiedler, D.; Leung, D. H.; Bergman, R. G.;
Raymond, K. N. Acc. Chem. Res 2005, 38, 349-358. (c) Fujita, M.;
Umemoto, K.; Yoshizawa, M.; Fujita, N.; Kusukawa, T.; Biradha, K. Chem.
Commun. 2001, 509-518. (d) Heinz, T.; Rudkevich, D.; Rebek, J., Jr.
Angew. Chem., Int. Ed. 1999, 38, 1136-1139.
Figure 1. (a) Cavitands used, and a representation of their folded state:
NaBH4, THF, 90%. (b) Illustration of the chiral environment created by
the hydrogen-bonding pattern at the rim; the exchange is slow on the NMR
time scale.
(3) (a) Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem., Int. Ed. 1991,
30, 1024-1027. (b) Makeiff, D. A.; Vishnumurthy, K.; Sherman, J. C. J.
Am. Chem. Soc. 2003, 125, 9558-9559. (c) Watanabe, S.; Goto, K.;
Kawashima, T.; Okazaki, R. J. Am. Chem. Soc. 1997, 119, 3195-3196.
(4) Dong, V. M.; Fiedler, D.; Carl, B.; Bergman, R. G.; Raymond, K. N. J.
Am. Chem. Soc. 2006, 128, 14464-14465.
The addition reaction of alcohols to carbonyls (eq 1, Figure
2) is reversible, and the formation of hemiacetals can be
unfavorable: aliphatic aldehydes form hydrates and hemiacetals
readily, but aromatic aldehydes and ketones typically do not.8
The entropic price of bringing the two reactants together is not
always compensated by the new covalent bonds formed. In the
case of intramolecular reactions, the entropic price is reduced,
and hemiacetals are readily observed; many examples are
(5) Yoshizawa, M.; Kusukawa, T.; Fujita, M.; Yamaguchi, K. J. Am. Chem.
Soc. 2001, 123, 10454-10459.
(6) (a) Goto, K.; Holler, M.; Okazaki, R. J. Am. Chem. Soc. 1997, 119, 1460-
1461. (b) Watanabe, S.; Goto, K.; Kawashima, T.; Okazaki, R. J. Am. Chem.
Soc. 1997, 119, 3195-3196. (c) Renslo, A. R.; Rebek, J., Jr. Angew. Chem.,
Int. Ed. 2000, 39, 3281-3283. (d) Park, T. K.; Schroeder, J.; Rebek, J., Jr.
J. Am. Chem. Soc. 1991, 113, 5125-5127.
(7) Iwasawa, T.; Hooley, R. J.; Rebek, J., Jr. Science 2007, 317, 493-496.
9
10.1021/ja0756366 CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 15639-15643
15639

A R T I C L E S
Hooley et al.
aldehyde peaks and so are not seen. Figure 3 shows the most
helpful peaks for assignment in the 1H NMR spectrum:
introverted alcohol CH2 (Hb/Hb′), cavitand benzimidazole proton
Ha, and the deeply bound guest methyl groups (Med/Med′)
Additional evidence for the covalent linkage is provided by mass
spectrometry. Electrospray ionization high-resolution mass
spectrometry (ESI-HRMS) of 2‚4 gives a mass of 2146.2626
(M + H+), which corresponds to that of the covalent adduct.
MS studies of noncovalently bound guests such as cyclohexane
show only disassociated cavitand and guest in systems such as
this. A modest diastereoselection occurs with a ratio of 1:0.6.10
Figure 2. The equilibria in question.
available in the chemistry of carbohydrates (eq 2, Figure 2).
The unfavorable additions give the initial intermediates for
formation of acetals, a process that can be driven to the products
by the removal of the side product, water.9
The isobutyraldehyde has modest affinity for 2, and some of
the cavitand exists in a flexible, partially folded state, resulting
in broad NMR signals. A 2D NOESY spectrum of the complex
(see Supporting Information) shows chemical exchange cross-
peaks between the broad guest signals at δ ) -2.4 and -2.7
and the signals for free isobutyraldehyde at δ ) 0.95, 0.75. No
exchange was seen between free isobutyraldehyde and the peaks
for either diastereomer of the hemiacetal. Also, Figure 4 shows
that the two diastereomers display no exchange between each
other, indicating that the hemiacetals are not undergoing
interconversion on the NMR time scale.11
Results and Discussion
Both of the components of the reaction (aldehydes and
alcohol) can be incorporated into the cavitand structure (Figure
1), allowing study of the equilibrium from two perspectives by
using alcohol or aldehyde guests, respectively. The introverted
aldehyde 1 was converted to the corresponding alcohol 2 by
reduction with NaBH4. These cavitands are held in the vase-
like conformation by the intramolecular hydrogen bonding, and
the cavities are large enough to surround a single small-molecule
guest and present it with the inwardly directed function. Both
cavitands 1 and 2 fold around a competitive solvent such as
CDCl3, but in solvents such as mesitylene-d12 that do not fit
inside, they show broad, undefined 1H NMR spectra. On
addition of small aldehydes such as propionaldehyde 3 or
isobutyraldehyde 4 to a solution of 2 in mesitylene-d12, the 1H
NMR spectra (see Figure 3 and Supporting Information) sharpen
considerably and show signals for bound guest. These appear
far upfield with shifts due to the magnetically shielded environ-
ment created by the many aromatic rings of the cavitand.
Integration of the signals for free and bound cavitand allows
determination of the equilibrium constant for hemiacetal forma-
tion. The calculation used the signals for the methine Ha which
are not broadened in the unoccupied cavitand. Other small
aldehydes also form hemiacetals inside cavitand 2, as shown
in Table 1. Propionaldehyde 3, n-butyraldehyde 5, and cyclo-
hexane carboxaldehyde 6 all form covalent complexes in
mesitylene solution, as seen by ESI-HRMS and the appearance
of characteristic 1H NMR peaks (see Supporting Information).
As the reactions do not reach equilibrium immediately, the
solutions were allowed to equilibrate over a period of 4 h before
NMR analysis. The smaller substrates (3 and 5) show no binding
without covalent bond formation, but 6 is a good guest even
without hemiacetal formation, and so two species can be seen
in the 1H NMR spectrum (see Supporting Information). Surpris-
ingly, there is no requirement for acid or base catalysis other
than that provided by the nearby secondary amidessor the
reactants themselves. The reaction takes place in a region of
organized weak hydrogen bonds in a nonpolar solvent, condi-
tions that contribute to the sluggish equilibration observed.
1
Further inspection of the H NMR spectrum shows that the
bound guest is coValently linked to the cavitand. Isobutyralde-
hyde shows no binding affinity for cavitand 1 (to which it cannot
form a covalent bond). When added to 2, three species are
formed (Figure 3): two sets of sharp signals corresponding to
the two diastereomers formed by covalent addition, and a set
of broad signals from a noncovalent complex. The diastereomers
arise from the new stereogenic center of the hemiacetal fixed
in a chiral environment. The seam of hydrogen bonds around
the rim of the cavitand can be either clockwise or counterclock-
wise and interconverts slowly on the NMR chemical shift time
scale (Figure 1b).6c (When the guests are noncovalently bound,
the complexes exist as two enantiomers and show only one set
of peaks.) Formation of a covalent complex locks the anthracene
arm over the top of the cavitand (in the unbound cavitand, the
arm is free to rotate), leading to a signature upfield shift in the
amide methyl groups. This orientation of the aromatic group
places the amides near the face of the anthracene, causing extra
shielding and resonances at δ ) -0.65 and -0.69 ppm. These
resonances are absent in species that do not form covalent
complexes (cyclohexane, cyclohexanol, etc.) The resonances for
new hemiacetal CH and OH are obscured by cavitand/free
We examined the solution counterparts to these systems to
arrive at a measure of the effects of the cavitand. In the absence
of the cavitand, a solution of 0.8 M of each aldehyde and benzyl
alcohol in deuterated benzene shows much smaller concentra-
tions of the corresponding hemiacetals in the NMR spectra. The
relative enhancement of the equilibrium, Keq/Kctrl, is shown in
Table 1, and varies from 13-fold for 5 to 138-fold for
isobutyraldehyde 4. It was also possible to observe enhanced
formation of a hemiketal. Upon addition of cyclohexanone to
2, a noncovalent complex forms on mixing. The hemiketal
grows in over a period of days to give roughly equal amounts
of covalent and noncovalent species. To our knowledge,
hemiketals of cyclohexanone are unreported in solution. As a
(8) (a) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry;
University Science Books: Sausalito, CA, 2006; Chapter 10. (b) Benzal-
dehyde has a very low Keq for hemiacetal formation in MeOH solvent:
Doddi, G.; Ercolani, G.; Mencarelli, P.; Scalamandre, C. J. Org. Chem.
1991, 56, 6331-6336. (c) Sander, E. G.; Jencks, W. P. J. Am. Chem. Soc.
1968, 90, 6154-6162.
(10) This ratio is similar to that seen in a related introverted ester: Purse, B.
W.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 2530-2534.
(11) (a) Hooley, R. J.; Rebek, J., Jr. Org. Lett. 2007, 1179-1182. (b) Hooley,
R. J.; Van Anda, H. J.; Rebek, J., Jr. J. Am. Chem. Soc. 2006, 128, 3894-
3895. (c) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem.
Soc. 1998, 120, 12216-12225.
(9) Finley, R. L.; Kubler, D. G.; McClelland, R. A. J. Org. Chem. 1980, 45,
644-648.
9
15640 J. AM. CHEM. SOC. VOL. 129, NO. 50, 2007

Cavitands with Introverted Functionality
A R T I C L E S
1
Figure 3. Selected regions of H NMR spectrum of hemiacetal formed by addition of isobutyraldehyde to alcohol 2.
Table 1. Enhancement of Equilibrium Constantsa for Various
Substrates
b
a Keq ) [hemiacetal]/([cavitand][guest]). Keq determined with [cavitand]0
c
) 1.5 mM and [guest]0 ) 10 mM. Kctrl for reaction of benzyl alcohol and
d
desired aldehyde in benzene-d6, [PhCH2OH]0 ) [RCHO]0 ) 0.8 M. Kctrl
for reaction of benzaldehyde and desired alcohol in benzene-d6, [PhCHO]0
) [ROH]0 ) 0.5 M. e [PhCHO]0 ) [ROH]0 ) 15 mM.
Figure 4. Expansion of the 2D NOESY spectrum of the complex 2‚4
formed by exposure of cavitand 2 to isobutyraldehyde 4, 600 MHz,
mesitylene-d12, 300 K, 300 ms mixing time. This region shows NOE cross-
peaks between benzyl protons Hb and Hb′ (same color), but no exchange
correlation between Hb of different diastereomers (different colors).
likely that the aldehyde arm was oriented outside the cavity, to
lower steric clashes with the guest. The equilibrium constant
for this process lies so far toward the reactants that even cavitand
binding does not reveal products at millimolar concentrations.
In an attempt to add further stabilization to the hemiacetal,8b,12,13
we introduced additional H-bonds using N,N-dimethylethano-
lamine 8, trans-1,2-cyclohexanediol 9, and trans-1,2-cyclopen-
tanediol 10.
result, a limit was estimated based upon the detection limits of
the spectrometer (Table 1), and enhancement of the addition
reaction inside 2 is >105.
Given the enhancements in equilibrium constant for the
addition of aldehydes to 2, we expected a similar effect for the
addition of alcohols to 1. Unfortunately, the addition of small
alcohols such as propanol, tert-butanol, and isoamyl alcohol to
a solution of 1 in mesitylene-d12 showed no folded cavitand,
even after 2 weeks. With larger alcohols that have better size
and shape complementarity for the cavitand (cyclohexanol,
cyclooctanol, and 1-adamantanol), host-guest complexes were
seen, but no visible hemiacetal formation occurred. No peaks
for upfield-shifted amide methyl groups were seen, so it is most
On addition of 10 equiv of alcohol 8 to 1, a new complex
was indeed formed. N,N-Dimethylethanolamine is a poor guest
for the cavity without covalent attachment, and so again two
species are present: the bound hemiacetal and unoccupied
cavitand, which displays broad, unassignable 1H NMR signals.
In this case, the resonance for the hemiacetal CH is not obscured
(12) Iwasawa, T.; Mann, E.; Rebek, J., Jr. J. Am. Chem. Soc. 2006, 128, 9308-
9309.
(13) Bone, R.; Cullis, P.; Wolfenden, R. J. Am. Chem. Soc. 1983, 105, 1339-
1343.
9
J. AM. CHEM. SOC. VOL. 129, NO. 50, 2007 15641

A R T I C L E S
Hooley et al.
(e.g., Figure 5b). There, the hydrogen-bonding benefit and the
stabilization are diminished but still significant.
Modeling indicates that the H-bond acceptor nitrogen in 1‚8
(Figure 5a) does not necessarily participate in an intramolecular
hydrogen bond with the hemiacetal OH; the NMe2 group is
positioned near the base of the cavity (as corroborated by their
1H NMR signals; ∆δ ) -3.6 ppm). Why the hemiacetal 1‚8 is
formed and other small alcohols show no reaction is unclear,
but evidently the newly formed OH is favored by its positioning
in the cavitand. Diols 9 and 10 most probably involve an extra
intramolecular H-bond to the second hydroxyl; in these cases,
the donor is not used to occupy the cavitand base. The extremely
slow rate of equilibration of 1‚10 can be rationalized by the
poor angle of attack of the larger guest. The mechanism of
hemiacetal formation (i.e., whether the nucleophilic addition
occurs before or after the binding event) is not clear and most
probably varies depending upon the nature of the guest. Diol
10 forms a kinetically stable noncovalent complex prior to
addition, and in that case, hemiacetal formation is significantly
slower than for guests 3-8. Orientation of the alcohol for attack
is unfavorable; thus, a large kinetic barrier to addition exists.
The smaller guests that do not preorganize the cavitand rely on
addition prior to rapid folding; this addition step has no
restrictions on angle of attack and so is faster, even though the
entropy of collision must be overcome.
Figure 5. Minimized representations of (a) hemiacetal derived from
combination of 1 and N,N-dimethylethanolamine 8 and (b) hemiacetal
derived from combination of 2 and isobutyraldehyde 4 (Maestro v. 7.0.2,
MMFFs forcefield).
by background and is seen as two singlets (for the two
diastereomers), δ ) 4.78 and 4.50 ppm. No coupling is seen to
the OH, which is consistent with the spectra for related
hemiaminals.7 The diastereomeric ratio in this case is 2:1. When
the equilibrium constant of hemiacetal formation in the cavitand
was calculated and compared to that for the reaction of
benzaldehyde and N,N-dimethylethanolamine, we were pleased
to see a significant enhancement in hemiacetal formation: Keq/
Kctrl ) 5800, far greater than observed for cavitand 2. The
presence of a second H-bond acceptor has an effect on these
equilibria in free solution: whereas no appreciable hemiacetal
formation was observed for the reaction of 0.5 M benzaldehyde
and cyclohexanol in benzene, the combination of 8 with
benzaldehyde gave barely observable amounts of hemiacetal,8b
allowing crude determination of the equilibrium constant.
N,N-Dimethylaminopropanol and 1,2-thiomethylethanol showed
no binding affinity or hemiacetal formation, but the cyclic diols
9 and 10 did form hemiacetals in cavitand 1 with Keq similar to
that of 7. In these cases, however, no hemiacetal formation was
observed in the control reaction with benzaldehyde; presumably
the OH group, being a weaker H-bond acceptor than NMe2,
does not provide enough stabilization of the hemiacetal to form
Conclusions
The introverted functions lead to direct observations of
intermediates in the liquid phase at ambient temperatures and
at equilibrium. The hemiacetal products of aldehydes and
alcohols can be observed in the cavitand and are significantly
amplified from their counterparts in free solution. Biological
macromolecules also use binding forces to stabilize reactive
intermediates, and covalent complexes have been proposed as
leading to the greatest rate enhancements.14 The concept of
enhancing the concentration of reactive intermediates offers
great potential for applications in supramolecular reactions and
catalysis.
1
Experimental Section
sufficient concentration to be visible by H NMR. As a result,
an upper limit was estimated on the basis of the detection limits
of the spectrometer (Table 1). This crude estimation leads to
large enhancements in Keq, possibly even larger than for 1‚8.
The formation of hemiacetals with 10 was extremely slow; only
after 4 days at 23 °C was equilibrium reached. In this case,
diol 10 is large enough to form a strong noncovalent complex
with 1 prior to hemiacetal formation, as seen by sharp signals
for folded cavitand (see Supporting Information).
How can the cavitand amplify the concentration of labile
species inside? The cavitand’s environment must preferentially
recognize and stabilize the tetrahedral intermediate through
hydrogen-bonding and other attractive interactions with the seam
of the cavitand’s amides. This situation is regarded as com-
monplace in biological catalysis, where the catalytic site is
capable of shifting equilibria toward unstable intermediates. The
adduct between 1 and 8, as shown in Figure 5a, positions the
new tetrahedral center particularly close to the amide rim, where
both hydrogen bond donors and acceptors are available and
permanently fixed in place through synthesis. The adducts with
cavitand 2 have their tetrahedral centers positioned deeper in
the cavity due to the extra methylene group on the anthracene
1D and 2D NMR spectra were recorded on a Bruker DRX-600
spectrometer. Proton (1H) chemical shifts, reported in parts per million
(ppm), were indirectly referenced to external tetramethylsilane employ-
ing resonances due to trace monoprotio solvent as an internal reference.
The 2D NOESY spectra of the cavitands were recorded at 300 K at
600 MHz with the phase-sensitive NOESY-GP pulse sequence including
a gradient pulse supplied with the Bruker software. Each of the 512
F1 increments was the accumulation of 36 scans. Before Fourier
transformation, the FIDs were multiplied by a 90° sine square function
in both the F2 and the F1 domains. 1K_1K real data points were used,
with a resolution of 1 Hz/point. Deuterated NMR solvents were obtained
from Cambridge Isotope Laboratories, Inc. (Andover, MA) and used
without further purification. High-resolution electrospray ionization
time-of-flight (TOF) spectra were acquired on an Agilent ESI-TOF mass
spectrometer. Anhydrous solvents were used as obtained from Acros
Organics. Guests 3-10, cyclohexanol, cyclooctanol, and 1-adamantanol
were obtained from Aldrich Chemical Co. and were used as received.
Cavitand 1 was synthesized according to the published procedure.7
Synthesis of Introverted Alcohol Cavitand 2. NaBH4 (10 mg, 0.26
mmol) was added to a solution of aldehyde 11 (24 mg, 11.6 µmol) in
(14) Zhang, X.; Houk, K. N. Acc. Chem. Res. 2005, 38, 379-385. Chen, J.;
Rebek, J., Jr. Org. Lett. 2002, 4, 327-329.
9
15642 J. AM. CHEM. SOC. VOL. 129, NO. 50, 2007

Cavitands with Introverted Functionality
A R T I C L E S
THF (5 mL) at 0 °C, and the resulting mixture was stirred for 30 min.
The reaction was quenched by addition of a saturated solution of NH4-
Cl (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined
organic phases were dried (MgSO4), filtered, and evaporated to give a
pale yellow solid. Flash column chromatograpy of the crude residue
(SiO2, CH2Cl2:EtOAc 4:1) afforded 2 as a white solid (21 mg, 90%):
1H NMR (600 MHz, CDCl3) δ 11.87 (s, 1H), 9.88 (s, 1H), 9.85 (s,
1H), 9.29 (s, 1H), 9.00 (s, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.43 (m,
1H), 8.12 (d, J ) 9.8 Hz, 1H), 8.08 (m, 1H), 7.95 (s, 1H), 7.93 (s,
1H), 7.85 (s, 1H), 7.78 (d, J ) 8.8 Hz, 1H), 7.72 (m, 1H), 7.63 (m,
1H), 7.51 (m, 3H), 7.43 (m, 2H), 7.35-7.14 (m, 11H), 5.79 (m, 3H),
5.65 (m, 1H), 4.48 (m, 2H), 3.72 (m, 1H), 2.61-2.13 (m, 14H), 1.85-
1.25 (m, 83H), 1.20 (t, J ) 8.4 Hz, 3H), 1.14 (t, J ) 8.4 Hz, 3H), 0.92
(m, 12H), 0.38 (t, J ) 8.4 Hz, 3H), 0.32 (m, J ) 8.4 Hz, 3H); HRMS
(ESI) calcd for C130H161N8O15 [M + H]+ 2074.2075, found 2074.2041.
ESI-HRMS analysis for hemiacetal 2‚6 (from alcohol 2 and
cyclohexylcarboxaldehyde 6): calcd for C137H173N8O16 (M + H+)
2186.2693, found 2186.2955.
ESI-HRMS analysis for hemiacetal 1‚8 (from aldehyde 1 and N,N-
dimethylethanolamine 8): calcd for C134H170N9O16 (M + H+) 2161.2759,
found 2161.2714.
ESI-HRMS analysis for hemiacetal 1‚9 (from aldehyde 1 and
(1R,2R)-trans-cyclohexanediol 9): calcd for C136H171N8O17 (M + H+)
2188.2756, found 2188.2724.
ESI-HRMS analysis for hemiacetal 1‚10 (from aldehyde 1 and trans-
cyclopentanediol 10): calcd for C135H169N8O17 (M + H+) 2174.2600,
found 2174.2607.
Determination of Equilibrium Constants.
General Procedure for Hemiacetal Formation. Aldehyde 1 (1.8
mg, 9 × 10-4 mmol) or alcohol 2 was dissolved in mesitylene-d12 (600
µL) and added to a 5 mM high-field NMR tube. Guest (aldehyde or
alcohol, ∼1.25 µL in 25 µL of mesitylene-d12) was added via syringe,
the NMR tube shaken to allow mixing, and the mixture analyzed by
1H NMR. After complete equilibration (4 h to 1 week), the complexes
were analyzed by 1H NMR and ESI-HRMS to determine Keq (see
below). The 1H NMR spectra (containing excess guest) for each product
are shown in the Supporting Information.
For the reaction above, Keq ) [HA]/([ROH][RCHO]), where [HA]
is the equilibrium concentration of hemiacetal, [ROH] is the equilibrium
concentration of alcohol, and [RCHO] is the equilibrium concentration
of aldehyde, all in M-1. Concentrations were measured by integration
of the appropriate signals in the 1H NMR spectrum after complete
equilibration had occurred.
Acknowledgment. We are grateful to the Skaggs Institute
and the National Institutes of Health (GM 27932) for financial
support. R.J.H. and T.I. are Skaggs Postdoctoral Fellows. P.R.
is a Knut and Alice Wallenberg Postdoctoral Fellow. We also
thank Drs. Laura Pasternack and Dee-Hua Huang for assistance
with NMR experiments.
Supporting Information Available: 1H NMR and NOESY
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
ESI-HRMS analysis for hemiacetal 2‚3 (from alcohol 2 and
propionaldehyde 3): calcd for C133H167N8O16 (M + H+) 2132.2494,
found 2132.2487.
ESI-HRMS analysis for hemiacetal 2‚4 (from alcohol 2 and
isobutyraldehyde 4): calcd for C134H169N8O16 (M + H+) 2146.2650,
found 2146.2626.
ESI-HRMS analysis for hemiacetal 2‚5 (from alcohol 2 and
butyraldehyde 5): calcd for C134H169N8O16 (M + H+) 2146.2650, found
2146.2638.
JA0756366
9
J. AM. CHEM. SOC. VOL. 129, NO. 50, 2007 15643