Origins of large rate enhancements in the nazarov cyclization catalyzed by supramolecular encapsulation

Article abstract of DOI:10.1002/chem.201303885

The self-assembled supramolecular host [Ga₄L₆] ^12- (1; L=N,N-bis(2,3-dihydroxybenzoyl)-1,5-diaminonaphthalene) catalyzes the Nazarov cyclization of 1,3-pentadienols with extremely high levels of efficiency. The catalyzed reaction proceeds at a rate over a million times faster than that of the background reaction, an increase comparable to those observed in some enzymatic systems. A detailed study was conducted to elucidate the reaction mechanism of both the catalyzed and uncatalyzed Nazarov cyclization of pentadienols. Kinetic analysis and ¹⁸O-exchange experiments implicate a mechanism, in which encapsulation, protonation, and water loss from substrate are reversible, followed by irreversible electrocyclization. Although electrocyclization is rate determining in the uncatalyzed reaction, the barrier for water loss and for electrocyclization are nearly equal in the assembly-catalyzed reaction. Analysis of the energetics of the catalyzed and uncatalyzed reaction revealed that transition-state stabilization contributes significantly to the dramatically enhanced rate of the catalyzed reaction. A self-assembled supramolecular host catalyzes the Nazarov cyclization of 1,3-pentadienols under mild, aqueous conditions. The catalyzed reaction rate is enhanced by a factor of over 10⁶ compared with the background reaction rate, one of the largest reported for supramolecular catalysis. Analysis of the reaction-energy profile revealed that transition-state stabilization contributes significantly to the dramatically enhanced reaction rate (see scheme).

Full text of DOI:10.1002/chem.201303885

DOI: 10.1002/chem.201303885
Full Paper
&
Host–Guest Systems
Origins of Large Rate Enhancements in the Nazarov Cyclization
Catalyzed by Supramolecular Encapsulation
Courtney J. Hastings,[a, b] Robert G. Bergman,*[a, b] and Kenneth N. Raymond*[a, b]
Abstract: The self-assembled supramolecular host [Ga4L6]12À
(1; L=N,N-bis(2,3-dihydroxybenzoyl)-1,5-diaminonaphtha-
plicate a mechanism, in which encapsulation, protonation,
and water loss from substrate are reversible, followed by ir-
reversible electrocyclization. Although electrocyclization is
rate determining in the uncatalyzed reaction, the barrier for
water loss and for electrocyclization are nearly equal in the
assembly-catalyzed reaction. Analysis of the energetics of
the catalyzed and uncatalyzed reaction revealed that transi-
tion-state stabilization contributes significantly to the dra-
matically enhanced rate of the catalyzed reaction.
lene) catalyzes the Nazarov cyclization of 1,3-pentadienols
with extremely high levels of efficiency. The catalyzed reac-
tion proceeds at a rate over a million times faster than that
of the background reaction, an increase comparable to
those observed in some enzymatic systems. A detailed study
was conducted to elucidate the reaction mechanism of both
the catalyzed and uncatalyzed Nazarov cyclization of penta-
dienols. Kinetic analysis and 18O-exchange experiments im-
Introduction
There are strong parallels between host–guest dynamics and
ligand–receptor interactions of biomacromolecules, and con-
siderable effort has been made to develop synthetic analogs
of important biochemical processes.[1] This analogy is even
more apt for self-assembled hosts; the three-dimensional struc-
ture of a protein is dictated by its primary amino acid se-
quence, while the structure of a self-assembled molecule is
programmed by the geometrical relationships and functional
groups present in each subunit. Enzymes, in particular, have
captivated chemists with their ability to catalyze reactions with
extremely high levels of selectivity and activity under mild,
aqueous conditions, and much effort has gone into developing
supramolecular catalysts that mimic enzymatic function.[2] Such
catalysts rely upon noncovalent interactions to provide the pri-
mary associative interaction between catalyst and substrate,
one factor that is responsible for the spectacular selectivity
and reactivity of enzymes.
Figure 1. Left: schematic view of 1, in which the bis-bidentate ligands are
represented by blue lines and the gallium atoms are represented by red cir-
cles. Right: space-filling model of 1.
guest molecules.[3] The host ligand framework generates
a large, hydrophobic interior cavity (250–450 ꢀ3) that can en-
capsulate guest molecules with binding affinities of up to
105 mÀ1.[4] The properties of 1 have been exploited to develop
reactions that occur inside the cavity of 1 with higher degrees
of reactivity than when the reaction is performed in bulk solu-
tion. For example, inclusion of reactive allyl enammonium cat-
ions in 1 greatly increases the rate of the 3-aza Cope rear-
rangement by binding a folded conformation of the reactant
that resembles the transition state of the reaction.[5] Encapsula-
tion in polyanionic 1 can perturb certain chemical equilibria to
favor the formation of cationic species, such as iminium ions
and labile phosphonium adducts.[6] This equilibrium shift also
applies to a wide range of protonated amines and phosphines
that are encapsulated in 1, even at strongly basic pH. The ef-
fective basicity of guest molecules is enhanced between 2.1
and 4.5 orders of magnitude. These investigations led to the
The self-assembled metal–ligand assembly [Ga4L6]12À (1; L=
N,N-bis(2,3-dihydroxybenzoyl)-1,5-diaminonaphthalene;
Fig-
ure 1) can act as a host for suitably sized cationic and neutral
[a] Dr. C. J. Hastings, Prof. R. G. Bergman, Prof. K. N. Raymond
Department of Chemistry, University of California
Berkeley, CA 94720-1416 (USA)
Fax: (+1)510-642-7714
Fax: (+1)510-486-5283
[b] Dr. C. J. Hastings, Prof. R. G. Bergman, Prof. K. N. Raymond
Lawrence Berkeley National Laboratory
1 Cyclotron Road, Berkeley, CA 94720 (USA)
E-mail: rbergman@berkeley.edu
raymond@socrates.berkeley.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303885.
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development of proton-catalyzed hydrolysis reactions inside 1,
in which a protonated transition state is stabilized in the host
interior.[7] These reactions are remarkable in that there are no
functional groups in the interior of 1; the protonation of
bound guests, as well as the transition states for their subse-
quent reactions, are favorable due to the charge of the host
assembly and cation–pi interactions with the naphthalene
rings of the host walls.[8] The stabilization of transient protonat-
ed species produces a several thousand-fold rate acceleration
of orthoformate and acetal hydrolysis under basic conditions.
We have communicated early studies of the Nazarov cycliza-
tion of 1,4-pentadien-3-ols (e.g., compound 2 in Scheme 1a–),
Table 1. Kinetic data for Nazarov substrates.[a]
Substrate
kcat [sÀ1
]
kuncat [sÀ1
]
Rate acceleration (kcat/kuncat)
2a[b]
2b
(2.9(4)ꢂ10À2
1.6(1)ꢂ10À2
5.7(1)ꢂ10À2
)
4.0(3)ꢂ10À8
7.7(8)ꢂ10À9
3.3(1)ꢂ10À8
(730000)
2100000
1700000
2c
[a] Reactions conducted at 458C in D2O/[D6]DMSO 1:1. Standard errors
are given in parentheses. [b] The kcat and rate acceleration values for sub-
strate 2a (in parentheses) were estimated from competitive binding ex-
periments with 2c (see the Supporting Information for a detailed discus-
sion).
tively with substrate (Scheme 1c). The unexpected formation
of dihydrofulvene 6 in the 1-catalyzed Nazarov cyclization of
symmetrical substrates 2a and 2b was recently disclosed
(Scheme 1d). The formation of 6 instead of its expected regio-
isomer 3 is the result of a kinetically controlled, regioselective
deprotonation of an intermediate cyclopentenyl carbocation.[11]
The regioselectivity of this deprotonation step is determined
by encapsulation within 1; no regioselectivity was observed
when the reaction was conducted in free solution. Herein, we
present mechanistic studies of the host-catalyzed Nazarov cy-
clization that were conducted to elucidate the reaction mecha-
nism of both the catalyzed and the uncatalyzed reaction.
Quantifying the energy profile of both reactions provides in-
sight into the dramatic and unprecedented rate acceleration of
the 1-catalyzed reaction over the uncatalyzed reaction.
Results and Discussion
Kinetic studies of the 1-catalyzed reaction
To probe the origin of the rate enhancement of the 1-cata-
lyzed Nazarov cyclization, mechanistic analysis of both the 1-
catalyzed and the uncatalyzed reaction were conducted, focus-
ing on whether the transition state of the rate-determining
step is stabilized by the constrictive interior of 1. Mechanistic
studies were conducted by using 2b as a substrate. Pseudo-
first-order consumption of starting material was observed
under 1-catalyzed conditions.[9] Variable-concentration kinetic
studies of the catalytic reaction revealed a first-order depend-
ence on [1] (Figure 2) and an apparent order of 0.5 on [D+]
(Figure 3, see below). The catalyst resting state was deter-
mined to be the encapsulated, neutral substrate 2bꢀ1 (in
which ꢀ denotes encapsulation) by 13C NMR analysis, and the
self-exchange rate[12] kexch of 2b in 1 is 2.4 sÀ1, which is fast rel-
ative to the overall rate of the 1-catalyzed reaction.[9] Kinetic
studies of the uncatalyzed reaction of substrate 2b were also
conducted; these display first-order dependence on both sub-
strate concentration and [D+] (Figure 4).[13] Additional data are
provided by the reactivity of the substrate 2-CF3 (Scheme 1b),
which is similar in size to 2b, but much less basic than 2b
owing to the electron-withdrawing trifluoromethyl substitu-
ent.[14] No reaction occurred when the 1-catalyzed Nazarov cy-
clization of 2-CF3 was attempted, although the expected host–
guest complex 2-CF3ꢀ1 was immediately formed. Taken to-
gether, these data implicate a mechanism that involves rapid,
Scheme 1. a) General Scheme for the Nazarov cyclization of pentadienols to
form cyclopentadienes. b) Pentadienol stereoisomers used in this study. c) 1-
Catalyzed Nazarov cyclization with maleimide (4) added to convert Cp*H (3)
to weakly binding Diels–Alder adduct 5, alleviating product inhibition.
d) Formation of unexpected dihydrofulvene isomer 6 from the 1-catalyzed
reaction of symmetrical substrates 2a or 2b.
a reaction that is catalyzed by supramolecular encapsulation
within 1.[9] The rate of the catalyzed reaction is up to 2100000
times larger than that of the uncatalyzed reaction, represent-
ing one of the largest reported rate accelerations for a reaction
catalyzed by supramolecular encapsulation (Table 1). This is
a rare example of supramolecular catalysis that achieves a level
of rate enhancement comparable to that observed in several
enzymes.[10] The reaction proceeds in aqueous or mixed water/
DMSO solution at near-neutral pH and mild temperature. The
reaction product, pentamethylcyclopentadiene (Cp*H, 3), is
a suitable guest for 1, and causes product inhibition when the
catalyzed reaction is carried out in mixed water/DMSO solu-
tion. Addition of maleimide to the reaction mixture traps Cp*H
as the corresponding Diels–Alder adduct 5, the binding con-
stant of which is low enough that it does not bind competi-
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Figure 2. Rate dependence on [1] for the 1-catalyzed Nazarov cyclization of
2b in 1:1 D2O/[D6]DMSO at 458C.
Figure 4. Rate dependence on [D+] for the uncatalyzed Nazarov cyclization
of 2b in 1:1 D2O/[D6]DMSO at 458C.
Scheme 2. Proposed mechanism in superacidic solution from Ref. [14].
18O-Incorporation studies
To determine the rate-determining step of the Nazarov cycliza-
tion, both the 1-catalyzed and the acid-catalyzed reaction of
2b were run to partial conversion in 18O-enriched water. No in-
corporation of 18O into the recovered starting material would
be expected if protonation or water loss is rate-determining,
whereas 18O incorporation would be expected if electrocycliza-
tion is substantially slower than recombination of carbocation
8a with water (Scheme 2). Incorporation of 18O into the recov-
ered starting material was observed in both reactions, proving
that protonation and water loss are reversible, and in the 1-
catalyzed case, confirming that encapsulation is reversible
(Table 2, entries 1–3). No 18O incorporation was observed when
the reaction is run at pD 8.0 in the absence of 1, ruling out
any pathway for 18O incorporation that does not involve acid
catalysis (Table 2, entry 4).
The rates of 18O incorporation versus the rate of product for-
mation are not equal for the 1-catalyzed and acid-catalyzed re-
action. When the 1-catalyzed reaction of 2b was run to 50%
conversion, 60% 18O incorporation was observed (Table 2,
entry 1). In the acid-catalyzed reaction, 90% 18O incorporation
was observed after only 10% conversion, and quantitative in-
corporation occurred after 50% conversion of 2b (Table 2, en-
Figure 3. Rate dependence on [D+] for the 1-catalyzed Nazarov cyclization
of 2b in 1:1 D2O/[D6]DMSO at 458C.
reversible binding of substrate, followed by protonation of the
bound guest. When the protonation step is made inaccessible
by using the less basic substrate 2-CF3, no reaction occurs.
Further studies of both the 1-catalyzed and the uncatalyzed
reaction were necessary, because these experiments do not
provide any information about the reaction mechanism
beyond the protonation steps, nor do they suggest which step
is rate determining. Earlier studies of the Nazarov cyclization
conducted in superacidic media implicate a mechanism in
which protonation and water loss is followed by rate-determin-
ing electrocyclization of a dienyl cation.[15] Upon quenching,
the resulting cyclized allyl cation is deprotonated to give the
product cyclopentadiene (Scheme 2). The relative rates of
these steps are certainly different under the superacid condi-
tions than they are in aqueous solution (1 catalyzed or acid
catalyzed); for example, 8a and 9a were observed by NMR in
superacid solution, but not in 1:1 D2O/[D6]DMSO at pD 8.0.
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Table 2. The Nazarov cyclization run in H218O/DMSO 1:1.
Entry
Catalyst
loading
pH
Reaction time
[min]
Conversion to
product [%]
18O label in
2b [%]
1[a]
2
3
4
10%
8.0
3.8
3.8
8.0
60
15
60
60
50
10
50
0
60
90
100
0
0
0
0
[a] Reaction run with maleimide co-substrate.
tries 2–3). One explanation for this difference in relative ex-
change versus cyclization rates is that the recombination of
8bꢀ1 with water is slower than the analogous reaction of un-
encapsulated 8b. It is possible that the effective concentration
of water inside the host cavity is lower than in solution, or that
8b is bound in a conformation that hinders recombination
with water. This effect was observed in a previous study, in
which the tropylium ion was protected from reacting with
water by encapsulation within 1, dramatically slowing the de-
composition rate of the tropylium cation compared to that ob-
served in free solution.[16] A second explanation is that encap-
sulation lowers the barrier for the electrocyclization of 8b.
Even slightly lowering the 7.1 kcalmolÀ1 barrier calculated for
the electrocyclization of 8b in the catalyzed reaction would ac-
count for the observed difference in 18O incorporation. It is not
possible to determine which one of these factors is responsible
for the 18O incorporation results, or whether both water recom-
bination and electrocyclization are affected by encapsulation.
However, it is clear that the barrier for the electrocyclization of
8bꢀ1 is lowered relative to the recombination of water when
compared to unencapsulated 8b. Additionally, these results in-
dicate that protonation and water loss are rapid compared to
electrocyclization in the uncatalyzed reaction, and that electro-
cyclization is rate determining. In the 1-catalyzed reaction, the
formation of product 4 and labeled reactant 2b-18O are com-
petitive, so the barrier heights for those two reactions must be
similar. That there is no single rate-determining step for the 1-
catalyzed reaction explains the unusual 0.5-order dependence
on [D+] observed in the 1-catalyzed reaction (Figure 3). These
results implicate a mechanism in which reversible substrate
binding, protonation, and water loss are followed by irreversi-
ble electrocyclization (Figure 5).
Figure 5. Proposed catalytic cycle for the 1-catalyzed Nazarov cyclization of
1,4-pentadien-3-ols, with 2a shown as a representative substrate.
Figure 6. Eyring plot used to determine activation parameters for the unca-
talyzed reaction of 2b (variable-temperature kinetics were conducted be-
tween 45 and 1058C).
DH° values for both reactions are within the standard error,
whereas the entropic barrier is reduced by 28 e.u. in the cata-
lyzed reaction relative to the uncatalyzed reaction. A lowered
entropic barrier is consistent with some degree of organization
in the transition state of the reaction being provided by encap-
sulation within 1; this is the effect that is responsible for cataly-
sis in the 1-catalyzed aza Cope rearrangement.[5] Protonation
of the neutral, encapsulated substrate (2bꢀ1) could also con-
tribute to the lowered entropic barrier; a large, positive
change in the entropy of hydration occurs when the host
charge is reduced from À12 to À11.[17] However, given that the
Activation parameters
The activation parameters for both the 1-catalyzed and the un-
catalyzed reaction of 2b were determined to gain additional
insight into the origin of the observed rate enhancements. The
measured activation parameters for the uncatalyzed reaction
of 2b are DH° =15.6(6) kcalmolÀ1 and DS° =À47(2) e.u.
(Figure 6), and the values for the catalyzed reaction of 2b are
DH° =14.8(8) kcalmolÀ1 and DS° =À20(3) e.u. (Figure 7). The
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thoformates.[7b,8c–e] Accordingly, it was estimated that the acidi-
ty of 7bꢀ1 is four pKa units higher than that of unencapsulat-
ed 7b, and that protonation of 2bꢀ1 is 12.7 kcalmolÀ1 uphill.
The cation-stabilizing ability of 1 stems from its large negative
charge and cation–pi interactions provided by the aromatic
rings that comprise the host walls. We assume that the ener-
getic value of water loss from 7bꢀ1 shown in Figure 8 is
4.4 kcalmolÀ1 uphill, as it is in the uncatalyzed reaction. How-
ever, stabilization of the dienyl carbocation 8b relative to 7b
by encapsulation is certainly possible; earlier studies demon-
strated that favoring tropylium in its equilibrium with proton-
ated 2,4,6-cycloheptatrien-1-ol by encapsulation in 1 could
play a role in slowing the decomposition of the tropylium
ion.[16b] Thus, the energy of 7bꢀ1 in Figure 8 is a rough esti-
mate. The activation energy of 21.3 kcalmolÀ1 for electrocycli-
zation of 8bꢀ1 was determined from the rate constant of the
1-catalyzed reaction. The free energy of 9aꢀ1 was estimated
by assuming moderate binding of 9a (binding energy of
À3.6 kcalmolÀ1 relative to unbound 9a, corresponding to 102
binding). Although this value is speculative, the binding con-
stant is unlikely to be below 10 or above 104, a range that in-
cludes the majority of cationic guests bound by 1,[3b,4a,17b,18]
and most guests bound by synthetic hosts in general.[19]
Figure 7. Eyring plot used to determine activation parameters for the 1-cata-
lyzed reaction of 2b (variable-temperature kinetics were conducted between
25 and 658C).
rate-determining steps for the 1-catalyzed reaction are differ-
ent than that of the uncatalyzed reaction, it is possible that
the measured activation parameters do not describe identical
chemical processes. Thus, the activation parameters for the
catalyzed and uncatalyzed reaction may not be directly compa-
rable.
In previous studies on the basicity enhancement of 1-bound
guests, the protonation equilibria of bound amines were shift-
ed by a maximum of 4.5 orders of magnitude, and the rate of
acid-catalyzed orthoformate hydrolysis was accelerated by
a maximum of 3.5 orders of magnitude. Based on this prece-
dent, it is clear that the acceleration of the 1-catalyzed Nazarov
cyclization is not simply due to increasing the basicity of the
bound substrate. According to the energetic values estimated
for the 1-catalyzed and uncatalyzed reaction, the reaction bar-
rier for electrocyclization of 8bꢀ1 is lowered by 3 kcalmolÀ1
relative to 8b (Figure 8). We considered that either encapsula-
tion within 1 could bind a reactive conformation of 2b that is
disfavored in bulk solution, or that encapsulation could stabi-
lize the transition state itself. Encapsulation in 1 and in other
supramolecular assemblies is known to favor folded conforma-
tions of acyclic molecules that are otherwise disfavored in bulk
solution,[3c,20] and conformational selection is responsible for
a nearly thousand-fold rate acceleration in the 1-catalyzed aza
Cope rearrangement of enammonium cations.[5] Examining the
rate constants for the uncatalyzed Nazarov cyclization of 2a, b,
and c indicates that substrate conformation affects the rate of
electrocyclization (Table 1); the reaction rate is slowest for 2b,
methyl groups of which are in the Z configuration. The cisoid
conformer of 8b necessary for rate-determining electrocycliza-
tion is sterically disfavored relative to the analogous cisoid con-
former of 8a. This effect is relatively small, only lowering the
reaction rate of 2b by a factor of five, relative to that of 2a,
Reaction-energy profile
To gain insight into the dramatic rate acceleration of the Naza-
rov cyclization that encapsulation in 1 provides, the energetic
profiles of the catalyzed and uncatalyzed reaction were esti-
mated and compared. The reactions of 2b were compared for
this purpose, because this substrate was used for the majority
of experimental studies. In the uncatalyzed reaction, a pKa of
À5.0 was estimated for protonated 2b (7b), based on compar-
ison to literature values. Accordingly, protonation of 2b under
the experimental conditions, pD 8.0, was estimated to be
18.9 kcalmolÀ1 uphill (for details on estimating the pKa of 7b,
and for determining the free energy of protonation, see the
Supporting Information), but was assumed to have a low addi-
tional kinetic barrier (Figure 8). The overall activation energy of
30.4 kcalmolÀ1 for rate-determining electrocyclization was de-
termined from the rate constant of the uncatalyzed reaction.
The free energy of intermediate carbocations 8b and 9a rela-
tive to the transition state of the electrocyclization (À7.1 and
À23.1 kcalmolÀ1, respectively) were predicted by DFT calcula-
tions (for details, see the Supporting Information).
The energetic values of binding 2b in 1 were determined
from the self-exchange rate of 2bꢀ1 (DGexch° =17.0 kcalmolÀ1
)
corresponding to an energetic difference of only 1 kcalmolÀ1
.
and the extent to which 2b is bound by 1 at the beginning of
the reaction (Figure 8 represents the beginning of the 1-cata-
lyzed reaction). Previous studies demonstrated that encapsula-
tion within 1 enhances the basicity of amines by up to
4.5 orders of magnitude, and that this basicity shift is responsi-
ble for thousand-fold rate enhancement in the hydrolysis of or-
Encapsulation in 1 could further lower the electrocyclization
barrier by stabilizing the compact transition state TS2. Based
on the small contribution of conformational selection towards
the overall rate acceleration, we conclude that transition-state
stabilization is the dominant factor in lowering the reaction
barrier 8bꢀ1 relative to 8b.
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Figure 8. Proposed reaction-coordinate diagram for the 1-catalyzed and the uncatalyzed Nazarov cyclization of 2b, showing relative energies at the begin-
ning of the reaction, at 318 K in 1:1 D2O/[D6]DMSO with K3PO4 (50 mm, pD 8.0), 1 (1.5 mm) and 2b (25 mm). Energies in italics were estimated (see text).
Conclusion
Experimental Section
General
Mechanistic studies of the 1-catalyzed Nazarov cyclization of
1,4-pentadien-3-ols were conducted, and comparisons were
made to the uncatalyzed reaction to understand the role of
encapsulation in this catalysis. Kinetic analysis of the reaction,
18O-exchange experiments, and computational studies imply
a mechanism in which encapsulation, protonation, and water
loss from substrate are reversible, followed by irreversible elec-
trocyclization. Although electrocyclization is rate determining
in the uncatalyzed reaction, the barrier for water loss and for
electrocyclization are nearly equal in the 1-catalyzed reaction.
Analysis of the proposed energetics of the catalyzed and unca-
talyzed reaction revealed that transition-state stabilization con-
tributes significantly to the catalytic rate acceleration. This, in
addition to the enhanced basicity caused by encapsulation in
1, is responsible for the dramatic million-fold rate enhance-
ment over the uncatalyzed reaction. Comparison of the activa-
tion parameters for the catalyzed and uncatalyzed reaction
supports the proposed origin of the rate acceleration.
Unless otherwise noted, all reactions and manipulations were per-
formed by using standard Schlenk and high-vacuum techniques at
room temperature. All glassware was dried in an oven at 1508C for
at least 12 h or flame dried under vacuum prior to use.
Instrumentation
NMR spectra were obtained on Bruker Avance AVQ 400 (400 MHz),
AV 400 (400 MHz), AV 500 (500 MHz), or AV 600 (600 MHz) spec-
trometers as indicated. Chemical shifts are reported as d in parts
per million (ppm) relative to residual protonated solvent resonan-
ces. In the case of D2O samples, 13C NMR shifts were referenced to
an internal standard of CH3OH.[21] Chemical shifts for 19F NMR data
were referenced to an internal standard of trifluoroethanol.[22] NMR
data are reported in the following format: (s=singlet, d=doublet,
t=triplet, q=quartet, m=multiplet, b=broad; integration; cou-
pling constant). The temperatures of the kinetics experiments car-
ried out in a circulating oil bath were measured by using a calibrat-
ed mercury thermometer and varied Æ0.18C. The temperatures of
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the kinetics experiments carried out in an NMR probe were deter-
mined from the 1H NMR chemical shifts of ethylene glycol and
CH3OH samples, and varied Æ0.18C. Mass spectral data were ob-
tained at the QB3 Mass Spectrometry Facility operated by the Col-
lege of Chemistry, University of California, Berkeley. Fast atom bom-
bardment (FAB) mass spectra were recorded on a Micromass ZAB2-
EQ magnetic sector instrument. Electron impact (EI) and chemical
ionization (CI) mass spectra were recorded on a Micromass ProSpec
magnetic sector instrument equipped with an EI and a CI source.
spectrum of the host–guest complex was recorded within 20 min.
No reaction was observed after the sample was heated at 508C for
5 h. Quantitative guest binding was not observed; the binding effi-
ciency is 77%, which represents the relative 1H NMR integrations
of the guest to host peaks. The unencapsulated guest is sparingly
1
soluble in D2O, and only broad resonances were observed. H NMR
3
3
(400 MHz, D2O): d=7.94 (d, 12H, J=7.7, Ar-H), 7.78 (d, 12H, J=
8.5 Hz, Ar-H), 7.34 (d, 12H, 3J=8.2 Hz, Ar-H), 7.01 (t, 12H, 3J=
8.1 Hz, Ar-H), 6.73 (d, 12H, 3J=7.2 Hz, Ar-H), 6.58 (t, 12H, 3J=
3
3
7.8 Hz, Ar-H), À0.90 (d, 3H, J=7.0, encaps.), À1.07 (d, 3H, J=7.0,
encaps.), À1.20 (s, 3H, encaps.), À1.29 ppm (s, 3H, encaps.);
19F NMR (376.5 MHz, D2O): d=À80.83 ppm.
Materials
Unless otherwise noted, reagents were obtained from commercial
suppliers and used without further purification. Ethyl ether (Et2O)
and tetrahydrofuran (THF) were dried by passing through columns
of activated alumina under nitrogen pressure and were sparged
with nitrogen before use.[23] K12Ga4L6 (K121), 2a, 2b, and 2c were
prepared according to literature procedures.[3b,9] (Z)-2-Bromo-2-
butene is occasionally available commercially from Sigma–Aldrich
and can be separated from the E isomer by preparative gas chro-
matography.[9]
General procedure for kinetic runs
In a typical experiment, the substrate (2.0 mg, 13.0 mmol), K121
(3.5 mg, 0.9 mmol), maleimide (2.0 mg, 20.6 mmol), and sodium p-
toluenesulfonate (3.0 mg, 15.4 mmol, added as an integration stan-
dard) were dissolved in [D6]DMSO (0.3 mL) and D2O (0.3 mL, buf-
fered with 100 mm phosphate buffer, adjusted to the desired pD).
The solution was transferred to an NMR tube and inserted into the
NMR probe preheated to 458C. After allowing the sample tempera-
Synthesis of 4-trifluoromethyl-3,5-dimethylhepta-2-trans-5-
trans-dien-4-one (2-CF3)
1
ture to equilibrate for two minutes, H NMR spectra were acquired
every 20 s, until >95% of the starting material was consumed.
This procedure was adapted for a small scale from a published pro-
cedure for the large-scale preparation of 2.[24] A two-necked round-
bottomed flask equipped with a magnetic stir bar and a reflux con-
denser was charged with lithium wire (155.5 mg, cut into 4 mm
lengths, 22.4 mmol) and dry Et2O (1 mL). (Z)-2-Bromo-2-butene was
purified and dried immediately before use by passage through
a pipette column of basic alumina. The first 0.7 mL of (Z)-2-bromo-
2-butene (total of 2.0 mL, 11.2 mmol) was added dropwise to the
stirred solution by syringe over the course of several minutes. At
this point, the reaction initiated, as was indicated by the evolution
of heat and bubbling of the reaction mixture. An additional por-
tion of fresh Et2O (10 mL) was added, and the remainder of the
bromide was added slowly to keep the reaction at reflux. After the
addition of the bromide was complete, an additional portion of
Et2O (5 mL) was added and stirring was continued for one addi-
tional hour. The reaction mixture was then cooled to 08C in an ice
bath and quenched by the slow addition of ethyl trifluoroacetate
(0.7 mL, 5.9 mmol) diluted to 50% with Et2O. The reaction mixture
was poured into saturated aqueous NH4Cl and extracted five times
with Et2O (20 mL). The combined organic layers were washed with
brine and dried over MgSO4, and the solvent was removed by
rotary evaporation to obtain the title compound (0.65 g, 3.1 mol)
as a yellow liquid in 56% yield and 85% purity. The contaminant is
The procedure for sample preparation for uncatalyzed reaction ki-
netics was analogous to that used for the catalyzed reaction,
except that 1 and maleimide were omitted and silylated glassware
was used. For experiments conducted at lower pD values (between
3.0 and 4.0), the aqueous portion of solvent was buffered with po-
tassium hydrogen phthalate (100 mm). The sample was sealed
under vacuum in a thin-walled NMR tube and heated at 458C in
a circulating oil bath.
18O-Labeling studies
The procedure for sample preparation was analogous to that used
for the kinetic studies: compound 2b (5.2 mg, 33.7 mmol), K121
(3.5 mg, 0.9 mmol), and maleimide (2.4 mg, 24.7 mmol) were dis-
solved in DMSO (0.3 mL) and [188]-water (0.3 mL, buffered with
100 mm phosphate adjusted to pH 8.0). The solution was trans-
ferred to an NMR tube and heated at 458C for one hour in a circu-
lating oil bath. A model reaction by using the same quantity of re-
1
agents in deuterated solvents was monitored by H NMR, and 50%
conversion of starting material was observed after one hour. After
heating, the reaction mixture was extracted three times with
0.5 mL portions of ethyl acetate. The combined organic phases
were washed three times with brine, dried over MgSO4, and fil-
tered. The resulting solution was analyzed by mass spectrometry
(CI) to determine the extent of 18O incorporation. The parent ion of
2 was not observed by other methods of mass spectrometry, such
as gas chromatography–mass spectrometry (GC-MS), EI, and FAB.
In these experiments, only dehydrated species were observed, and
18O incorporation could not be determined. For the acid-catalyzed
and the uncatalyzed reactions, the above-described procedure was
followed, except that 1 and maleimide were omitted. [188]-Water
was buffered with potassium hydrogen phthalate (100 mm) for the
acid-catalyzed reaction. A model reaction by using the same quan-
tity of reagents in deuterated solvent (aqueous portion buffered to
1
3
the E,Z stereoisomer. H NMR (400 MHz, CDCl3): d=5.52 (q, 2H, J=
7.3 Hz), 1.87 (s, 6H), 1.60 ppm (d, 6H, 3J=7.2 Hz); 13C{1H} NMR
2
(100.6 MHz, CDCl3): d=134.1, 128.7, 126.5 (q, 1C, JFC =150 Hz) 78.8
(q, 1C, 3JFC =28 Hz), 22.3 (q, 2C, 4JFC =2.7 Hz), 18.3 ppm; 19F NMR
(376.5 MHz, CDCl3): d=À77.58 ppm (E,Z stereoisomer at
À76.12 ppm); HRMS (EI): elemental analysis calcd (%) for C10H14F3O
[MÀH]+: 207.0997; found: 207.0998; elemental analysis calcd (%)
for C10H15F3O [M]+: 208.1075; found 208.1067 (50% intensity with
respect to [MÀH]+).
Synthesis of K12[2ÀCF3ꢀ1]
1
The potassium salt of 1 (15.0 mg, 4.0 mmol) was dissolved in D2O
(0.6 mL, buffered to pD 8.0 with 0.1m KH2PO4), and the resulting
solution was then mixed thoroughly with 2-CF3 (2.5 mg,
12.0 mmol). The solution was transferred to an NMR tube, and the
pD 3.4) was monitored by H NMR spectroscopy, and 10% conver-
sion of starting material was observed after fifteen minutes, where-
as 50% conversion of starting material was observed after one
hour.
Chem. Eur. J. 2014, 20, 3966 – 3973
www.chemeurj.org
3972
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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DFT calculations
All calculations were carried out in the UC Berkeley Molecular
Graphics and Computational Facility by using the Gaussian 03 soft-
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Acknowledgements
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The authors would like to thank Dr. Jamin Krinski and Dr.
Kathleen Durkin for assistance with DFT computational studies,
and acknowledge NSF Grants CHE-0233882 and CHE-0840505,
which fund the UC Berkeley Molecular Graphics and Computa-
tional Facility. We also thank Dr. Ulla Andersen for obtaining
MS data and Prof. Michael Pluth for helpful discussions. We ac-
knowledge financial support from the Director, Office of Sci-
ence, 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–
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Keywords: carbocations
reaction mechanisms · supramolecular chemistry
· catalysis · electrocyclization ·
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Received: October 3, 2013
Published online on February 25, 2014
Chem. Eur. J. 2014, 20, 3966 – 3973
www.chemeurj.org
3973
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim