Au-Cavitand Catalyzed Alkyne-Acid Cyclizations

Article abstract of DOI:10.1002/ejoc.201900829

Supramolecular cavitands that contain inwardly directed functional groups have yielded specialized transformations and trapping of reactive intermediates. A recently reported 3-wall Au cavitand provides exciting opportunities for supramolecular catalysis. In this study, a variety of substituted γ-alkynoic acids were reacted to give lactones. The interaction of peripheral “R” groups revealed differential catalyst behavior. Extremely large and small groups reacted with appreciable rate. Intermediate sized groups however, slowed significantly: giving support that size-specific binding is at play when using cavitands as a scaffold for gold catalysis. These results serve as some of the first evidence of the interplay between substrate and cavitand interior in the catalytic sphere.

Full text of DOI:10.1002/ejoc.201900829

A Journal of
Accepted Article
Title: Au-Cavitand Catalyzed Alkyne-acid Cyclizations
Authors: Tam D. Ho and Michael P Schramm
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900829
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900829
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10.1002/ejoc.201900829
European Journal of Organic Chemistry
COMMUNICATION
Au-Cavitand Catalyzed Alkyne-acid Cyclizations
Tam D. Ho and Michael P. Schramm *[a]
Dedication: To Julius, in appreciation of your mentorship, on the occasion of your birthday – this one’s for you.
Abstract: Supramolecular cavitands that contain inwardly directed
functional groups have yielded specialized transformations and
trapping of reactive intermediates. A recently reported 3-wall Au
cavitand provides exciting opportunities for supramolecular catalysis.
In this study, a variety of substituted γ-alkynoic acids were reacted to
give lactones. The interaction of peripheral “R” groups revealed
differential catalyst behavior. Extremely large and small groups
reacted with appreciable rate. Intermediate sized groups however,
slowed significantly: giving support that size-specific binding is at play
when using cavitands as a scaffold for gold catalysis. These results
serve as some of the first evidence of the interplay between substrate
and cavitand interior in the catalytic sphere.
Organocatalysis was achieved using an inwardly directed acid
that cyclized 5-hydroxy-pent-1-eneoxides, 100-fold rate
enhancements as well as selective 5-exo products were formed.9
We find two reports with metals particularly inspiring. A cavitand
outfitted with palladium catalyzed allylic alkylation reactions10 and
catalysis of choline to acetyl choline was predicated on choline
binding inside a cavitand adjacent to a Zn–salen wall.11 A much
earlier report installed four AuCl centers onto a shallower
resorcinarene that had bridging phosphonito groups.12
More recently and much more broadly supramolecular science
has taken many common themes and explored ways to study
catalysis. One approach has been to use very bulky phosphine
“end caps” to coordinate to Au•triflamide. The resulting catalyst
has hole-like topology and displays very special reactivity
compared to electronically similar, albeit smaller ligands
(incapable of providing a hole/pocket).13 There are other ways to
provide reactants holes to find metal centers buried in,
cyclodextrins with a proximal NHC ligand have provided a
platform to install Cu, Ag and Au. Regioselective hydroboration
depends on CD size and more deeply a change in mechanism.14
Gold on the other hand could affect enyne cyclization, including
examples where the CD pocket gave ee.15 Another approach has
taken supramolecular structures and non-covalently included a
reactive center via host-guest principles. A tetrahedral assembly
of six bisbidentate ligands and four Ga centers provided an
enticing environment for Me3PAuCl, which then catalyzed
intramolecular hydroalkoxylation of allenes.16 Returning to
resorcinarene, the remarkable self-assembly of six units provides
a very large environment within which to work.17 NHC-Au
catalysts provide relevant points to consider, as their catalytic
activity drastically changes inside the hexamer.18-20 These themes
have been more carefully elaborated on in a series of recent
reviews.21-24
Introduction
Natural receptors and enzymes have a variety of features that
have attracted attention from many areas of the chemical
community. Supramolecular chemists in particular draw
multifaceted inspiration from these entities. The first salient
feature is a well-defined internal space, often hydrophobic in
nature, and ultimately suitable for a specialized guest molecule.
Paradigms for recognition of guests emerged from biological
archetypes: 1) Fischer’s lock and key1 and 2) Koshland’s induced
fit.2 Synthetic receptors have taken the forms of cages and vases
of a variety of sizes, shapes and functions. We know some of
them as “cavitands,”3 “cryptands,” “carcerands,” and “capsules”4
(to name a few of the ones that start with the letter c!). Logically
nature provides one set of rules for all hosts and synthetic ones
have afforded direct observation of physical chemical
phenomenon by techniques like NMR that can relate either
forward from or backward towards their natural counterparts. The
second important feature of enzymes that inspire us is that they
perform numerous specialized chemical transformations.
Returning to this contribution, the “inwardly directed phosphorous”
3-walled cavitand 1 plays significant role (Scheme 1).25 1 afforded
complexation with Au-Cl, placing a gold metal center directly
inside the aromatic walls of a well-defined and characterized (by
x-ray) binding pocket.26 Catalysis screening ensued with 2; both
hydration of alkynes as well as Conia-ene reactions were
performed. These first modest reports demonstrated some
potential for general cavitand catalysis. The role of the cavitand
itself remains open for exploration. 2-wall bis-gold cavitands27-29
Resorcinarene cavitands have steadily been explored as a
relevant synthetic platform to explore the possibilities of catalysis.
The first antecedents employed Kemp’s triacid and successfully
placed a carboxylic acid “inwardly directed.” The bound lifetime of
amines increased5 and the racemization of a chiral amine was
stopped.6 A further variation used an inwardly directed aldehyde
to directly observe an otherwise labile hemiaminol intermediate.7,
31
and 2-wall mono-gold mono-phosphorous oxide cavitands30,
followed quickly and these species point to a role of intermediate
stabilization as well as the importance of correct spatial-
positioning. They have been added to a very recent review that
encompasses earlier mentioned topics as well as the most recent
approaches (e.g. using M12L24 cages).32
[a]
Prof. Michael P. Schramm, Ph.D.
Department of Chemistry and Biochemistry, California State
University Long Beach (CSULB), 1250 Bellflower Blvd. Long Beach,
CA 90840, USA
michael.schramm@csulb.edu
https://schrammlab.wordpress.com/
Herein we report that new opportunities for the three-wall variation,
2 continue to emerge. We report that γ-alkynoic acids with a
variety of R groups behave differently than each other, but do not
follow the fundamental principles of sterics that we are used to
(e.g. large is slow, small is fast). Instead, when the cavitand acts
Supporting information for this article is given via a link at the end of
the document
8
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10.1002/ejoc.201900829
European Journal of Organic Chemistry
COMMUNICATION
as the catalyst, R group size matters most likely related to host-
guest chemistry. Guests that contain specific molecular fragments,
ones that have previously been demonstrated to be good guests
for 4-wall cavitands (e.g. benzyl sized) slowed reactions. This
happens when they decorate the periphery of an otherwise
suitable substrate. Small (e.g. propargyl) and large (e.g. octyl,
napthyl, 3,5-dimethylbenzyl) R-groups, behave similarly to one
another, without slowing.
O
O
HO
R
R
O
O
OH
H
O
O
R'
O
OH
R'
H
H
O
O
OR
R
R'
OR
Au
N
N
N
N
N
P
N
O
N
O
O
O
O
O
O
O
Cl
N
N
Au
N
N
AuCl•S(Me)2
N
N
(H3C)2N
N
(H3C)2N
N
P
P
N
O
N
O
N
N
O
O
O
O
Scheme 3. Potential modes of host-guest recognition.
O
O
O
O
CH2Cl2
30 min
O
O
O
O
O
O
99%, x-ray
C11H
C11
H
23 C11H23
23 C11H23
C11H23
C11H23
C11H23
C11H23
Scheme 4 outlines the requisite procedures for a small library of
compounds (for full details see Supporting information). In short,
malonates were either mono or dialkylated with propargyl bromide.
In the case of monoalkylation, a second group was installed in a
subsequent step. Statistical ester removal was performed using
KOH when R = Me and TFA when R = tBu. All compounds were
characterized by NMR spectroscopy and rigorously purified
before being subject to catalytic screening. t-Butyl ester alkyne-
acids with dipropargyl (10), n-octyl (11) and benzyl (12) R’-groups
were prepared. Methyl analogs to dipropargyl (13), n-octyl (14)
and benzyl (15) were prepared. A subset of substrates 16-19 were
prepared after initial screening of 10-15.
2
1
Scheme 1. 3-wall resorcin[4]arene cavitands: Inwardly directed
Phosphorous 1 and Gold-Cl 2.
Results and Discussion
The gold catalyzed cyclization of γ-alkynoic acids has been
previously reported (Scheme 2).33 A variety of R groups on
methylester-acid-alkyne
3
were well tolerated at room
temperature with mol% of AuCl (9 examples, 75-97%
5
conversion). Product 4 is typical, and improvements to this work
O
O
Br
O
O
are ongoing.34
R'-LG
RO
OR
RO
OR
R = Me, t-Bu
CsCO3
acetone
K2CO3
Acetone
7
O
CH3
6
O
O
O
O
O
O
AuCl, 5%
CH3
O
O
O
HO
KOH (R = Me)
TFA (R = t-Bu)
O
HO
OR
RO
OR
R'
R
R'
ACN,
20°C 2h
Ph
4
90%
9
8
3
O
O
O
O
HO
OtBu
Scheme 2. “Au(I)-Catalyzed exo-Selective Cycloisomerization of Acetylenic
HO
OMe
O
O
O
O
Acids.”33
HO
OMe
HO
OMe
10 2 steps 26%
13 2 steps 17%
The straightforward preparation of mono-acid alkynes 3 and our
3-walled Au cavitand 2 led us to consider the effect of spectator
“R” groups on reactivity. Could flanking “R” groups play a role in
recognition that translates into a change in rate of cyclization?
Scheme 3 illustrates a generic substrate 5, were we note two
points of variation, R and R’. If the cavitand prefers either
spectator or the alkyne, does it alter the outcome? We prepared
several substrates with the hopes of uncovering variables that
result in differential outcome based on host-guest chemistry
principles. We wondered if the alkyne is always the most
kinetically accessible? If so then R and R’ should play no role.
Conversely would a R or R’ recognition event speed up, slow or
stop a reaction?
O
O
O
O
HO
OtBu
C8H17
HO
OMe
C8H17
18 3 steps 15%
16 3 steps 14%
O
O
O
O
11 3 steps 6%
14 3 steps 22%
HO
OMe
HO
OMe
O
O
O
O
HO
OtBu
HO
OMe
17 3 steps 12%
19 3 steps 10%
15 3 steps 31%
12 3 steps 8%
Scheme 4. Preparation of substitude alkyne-acids and collection of substrates
for screening. t-Butyl alkyne-acids, 10-12 and Methyl alkyne-acids 13-18, with
three step isolated yields (full details in ESI).
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10.1002/ejoc.201900829
European Journal of Organic Chemistry
COMMUNICATION
larger (10-12) than methyl (13-15) and prevents the alkyne from
accessing the Au cavitand 2, or the t-butyl group has some direct
interaction with the cavitand interior that the methyl group does
not. These scenarios could alter the time or orientation that the
alkyne group has with the Au center and thus reactivity slows. We
leave this point unresolved, as a more compelling series of results
emerges when we look at R’.
The benzyl group found in 12 and 15 has more steric bulk than
the dipropragyl (10 and 13), but isn’t n-octyl (14, 11) as
cumbersome as benzyl? To explore if this was simply a steric
effect where bulk prevents the alkyne from finding gold we
Owing to limited solubility of cavitand 2 in acetonitrile, we
conducted a first round of catalyst screening in Chloroform and
Toluene at 23 and 70 °C. Percent conversion was calculated by
1
integration of H NMR; only starting material and product peaks
were observed in the transformation of terminal alkyne to lactone
(see Scheme 2). 23 °C proved to be too slow for practical use, no
substrates were completely converted to lactone after 48 hours in
the presence of 4 mol% 2: 13 (63%), 14 (47%) and 15 (21%). At
70 °C the reactions were fast enough to monitor over a 24-hour
period and ultimately provided a means to identify differences
(Table 1). Other additives are known to accelerate these reactions, prepared a second generation of substrates that vary the size of
which we will discuss in a future paper. Table 1 illustrates the
results of this initial screening at 70 °C. Reactions of substrate 13
containing two propargyl groups was very efficient, coming to
completion after 4 hours. When R’ = n-octyl (14) an additional 20
hours was required. The dipropargyl substrate 13 likely has more
efficient conversion than 14 owing to an additional reactive alkyne
center being present. When R’ = benzyl (15) the reactions were
markedly slower than 14. Especially at later time points (e.g. 4, 24
hr). For the uninitiated reader, benzyl is a known guest for
resorcinarene cavitands and in non-completive solvents can be
observed inside by NMR.
the aromatic R’ group with respect to 15. As illustrated in Scheme
4, R’ 1-naphthyl 16, 3,5-dimethylbenzyl 17 and
=
propenylbenzene 18 were prepared. If steric repulsion is the
primary director, then these substituents should be equally slow
to 15, if not more so. Of note to the reader is that substituted
naphthyls as well as xylene-like or mesitylene-like substrates are
not particularly good guests for resorcinarene cavitands. Their
girth prevents effective entrance into the cavitand, this led early
pioneers in the field to use mesitylene-d12 as an NMR solvent, so
as to exclude it from competing with guests for cavitand3 and
capsule interiors.35 Indeed chloroform, benzene, and para-
disubstituded aromatics have been extensively studied in
resorcinarene capsules, where they can be directly observed to
habitate.36, 37
Table 2 shows the results of these benzyl analogs in 3 different
solvents at 70 °C. First examination in chloroform reveals that 1-
naphthyl and 3,5-dimentyl benzyl are faster than benzyl, while the
longer benzyl variant, namely propenylbenzene was slower.
Toluene is a suitable guest for cavitand interiors and when it was
used as the reaction solvent, napthyl 16 and 3,5-dimethylbenzyl
17 are the fastest, benzyl 15 and propenylbenzene 18 are slower,
but all are similar (74-100% after 24 h). Finally, in mesitylene – a
solvent that can’t appreciably occupy the cavitand we see the
largest guests continue to convert the fastest but this time there
is an inversion for the slowest, benzyl 15 wins. The observation
that the largest substituents react with similar profiles in different
solvents supports the idea that they do not fit inside and thus the
reactive centers are free to react. When the side-chain is
suspected to fit inside, the reactivity slows in a variety of solvents,
more so in non-competing solvents.
Table 1. First Screen: Effect of Solvent, side chain R’ and ester R on the
cyclization of alkyne-acids 10-15 (0.12 M) with gold cavitand 2 (4 mol%). Bold
entries indicate effective reaction completion time point, beyond which little
conversion was observed.
CDCl3
Substrate
R= t-butyl,
R’ =
Substrate
R= Me,
R’ =
CDCl3
Toluene-d8
Time
70 °C
63%
84%
99%
70 °C
50%
69%
98%
70 °C
24%
36%
64%
96%
60%
69%
77%
77%
23%
31%
52%
53%
1 hr
2 hr
4 hr
24 hr
1 hr
2 hr
4 hr
24 hr
1 hr
2 hr
4 hr
24 hr
10
13
Dipropargyl
Dipropargyl
28%
46%
92%
94%
20%
35%
58%
67%
20%
37%
70%
96%
17%
20%
24%
81%
11
n-octyl
14
n-octyl
12
benzyl
15
benzyl
Within Table 1 we also compare the effect of the t-butyl ester
group. We note a slowing of conversion compared to the smaller
methyl R group. The bulkier ester group could play one of two
plausible roles in the decreased rate of reaction. Either it is simply
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10.1002/ejoc.201900829
European Journal of Organic Chemistry
COMMUNICATION
Table 2. Effect of side chain R’ size with larger aromatics on the cyclization of
alkyne-acids 15-18 (0.12M), 70 °C, in Chloroform, Toluene and Mesitylene, with
4% of gold cavitand 2. Entires from Table 1 for ease of comparison are noted,[a]
bold entries indicate effective reaction endpoint.
k1
A
P
(equation 2)
k-1
Substrate
R = Me, R’ =
Toluene-
d8
Mesitylene-
d12
Given many possible kinetic treatments,39, 40 we first assumed that
substrate A would behave under pseudo 1st order conditions, as
the catalyst concentration is both low (4.0 mol %) and constant (at
the end of the reaction the NMR of 2 is unchanged and
characterizable with ~4 pulses). Equation 3 provides the usual
representation of this assumption, where I represents a reversibly
formed intermediate (in this case a host-guest complex), that
irreversibly goes to product P.
Time
CDCl3
1 hr
2 hr
4 hr
24 hr
1 hr
2 hr
4 hr
20%[a]
35%[a]
58%[a]
67%[a]
27%
17%[a]
20%[a]
24%[a]
81%[a]
31%
5%
6%
15
benzyl
7%
39% slowest
28%
k1
k2
(equation 3)
A
I
P
37%
45%
41%
k-1
16
1-naphthyl
58%
71%
76%
Applying the steady state approximation, such that the change in
[I] with time = 0, and that under the current reaction conditions,
product formation is irreversible (i.e. k-2 = 0, equation 3), the rate
equation can take the simplified form (equation 4).
100%
fastest
99%
fastest
81%
24 hr
1 hr
2 hr
4 hr
22%
30%
55%
23%
32%
56%
19%
57%
74%
ꢈꢉ ꢊ
ꢆꢁꢇꢂ =
= ꢌobs[A]
(equation 4)
ꢈꢉꢋ
17
3,5-
dimethylbenzyl
Where ꢌobs encompasses [cat], ꢌ1, ꢌ-1, and ꢌ2. Based on our initial
conversion data (Table 1 and Table 2), when we collected much
more detailed “real-time” integral data many expected variations
were observed (Table 3) (See ESI for NMR conditions, raw data
and curve fits).
83%
fastest
24 hr
95%
87%
1 hr
2 hr
4 hr
20%
28%
32%
17%
20%
25%
22%
27%
34%
Table 3. Kinetic Analysis: Alkyne-acids (0.12 M) and gold cavitand 2 (4 mol%)
were mixed in chloroform and monitored over 24 hours at 55 °C. kobs reported
in s-1, r Error as the root mean square between the fit and raw data and Turn
Over Number at the end of reaction (24 h).
18
propenyl
benzene
36%
slowest
74%
slowest
24 hr
66%
Substrate
kobs (s-1)
r Error
TON
21.4
23.9
24.5
13.0
17.7
1-napthyl (16)
8.56E-05
2.54E-05
2.24E-05
8.87E-05
5.59E-05
8.09E-07
4.33E-07
7.60E-07
2.86E-06
9.69E-07
To further elucidate the role structure vs. reactivity as well as we
conducted a series of detailed kinetics experiments. Substrates
15-18 and a previously unstudied p-methyl benzyl 19 were
dissolved (0.12M) in CDCl3 in the presence of 4 mol% of 2.
Samples were mixed and inserted (at t=120 s) into a pre-warmed
(328.2K) NMR. The instrument was shimmed twice as the sample
equilibrated and after 300 seconds of heating 30-35 spectra were
acquired at nonlinear intervals over 24 hrs. The data was
processed carefully and plots of concentration vs. time were
generated. The data was fit to a 3-parameter exponential function
(equation 1), after first trying many others.38
dimethylbenzyl (17)
p-Methylbenzyl (19)
Propenylbenzene (18)
Benzyl (15)
First, substrates 16, 17 and 19 all approach completion (21.4-24.5
TON, theoretical max = 25), but at different rates. This was
obvious visually from the raw data. Benzyl 15 has an observed
rate constant between 16 and 17 but the reaction has
disappointing turn over (17.7). Finally, propenylbenzene 18
mimics the rapid decline of substrate concentration similar to
napthyl 16, reflected in ꢌobs, but the turnover is much lower (13.0
vs 21.4).
This data reinforces our initial findings in Tables 1 and 2, R’
groups are playing a significant role in how the reactive functional
groups are allowed to interact with the catalyst. 19 was anticipated
to behave like 15 and 18, as toluene is a known guest for
resorcinarene cavitands, we expected marked slowing of the
ꢀ = ꢁꢂꢃꢄ + ꢅ
(equation 1)
This function gives b as the exponential component and c is an
offset that can take on many possible variables including
instrumental artifacts, miscalibration, or as written this function
can be applied to first order decay of a reactant as it approaches
equilibrium (equation 2). At first glance this is an oversimplification,
but the initial results already point to differential binding events
which may or may not include equilibration.
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10.1002/ejoc.201900829
European Journal of Organic Chemistry
COMMUNICATION
lactonization. But when we carried out the study this shape
behaved similarly to dimethylbenzyl 17 which can not fit inside a
cavitand. At this stage we applied a more recently developed
with competition partner 16 a deceleration of reaction was again
observed. After 24 hours only 42% of the substrate was converted
into lactone 20 (typically 81%, Table 2). These results support a
possibility that lactone 20 is an inhibitor for catalyst 2.
series of kinetic tools. Reaction Progress Kinetic Analysis
42
(RPKA)41,
and Visual Kinetic Analysis43, 44. RPKA has been
O
O
O
O
O
O
O
O
O
deployed successfully to resolve many kinetic issues including
O
4 mol%
2
HO
OMe
OMe
HO
OMe
OMe
+
+
determining order of substrate, order of catalyst, catalyst
CDCl3, 70°C
46
decomposition and catalyst inhibition.45,
Using RPKA we
21
20
15
16
confirmed the kobs reported in Table 3, taking the derivative of the
3-parameter exponential function and plotting against substrate
concentration gave a straight line in each case, matching the kobs
with R2 values of 0.989-1.0 (see ESI). We next repeated the
kinetic analysis of 15 at 0.09 M and 0.06M concentrations. When
we used time shifted Visual Kinetic Analysis we did not observe
curve overlap especially when comparing 0.12M vs. 0.06M. If we
had observed overlap then we can infer no product inhibition and
no catalyst deactivation. This initial observation points to one of
these possibilities. The same information can be retrieved by
plotting the first derivative vs [A] (RPKA). We found that kobs
increased and TON decreasing with decreasing substrate
concentration (Table 4). Again these results point to either product
inhibition or catalyst deactivation. We believe these results also
could be the result of substrate inhibition, which RPKA hasn’t
addressed to our knowledge as “same excess” experiments
require two reactants to carry out. As both reaction partners exist
in our substrates, the same excess experiment can’t be performed
precisely as prescribed.
1 h: 20%
1 day:
22%
73%
75%
O
O
O
O
O
O
O
O
4 mol%
2
HO
OMe
OMe
OMe
+
CDCl3, 70°C
1 h: 9%
1 day: 11%
20
20 (1eq)
15 (1eq)
O
O
O
O
O
O
O
O
4 mol%
2
HO
OMe
OMe
OMe
+
CDCl3, 70°C
1 h: 21%
1 day: 42%
21
20 (1eq)
16 (1 eq)
Scheme 5. Direct competition of 15 and 16 and reaction doping with lactone
20. Conversion % is reported from 1H NMR integration, all 4 species had cleanly
resolved peaks. Conversion is reported per substrate and is = (product area /
(product area + substrate area). Product/substrate competition of 20 with 15:
conversion % is reported from 1H NMR integration of additionally formed product
originating from 15. Product/substrate competition of 20 with 16, conversion is
reported as 16 become 21.
Table 4. Kinetic Analysis: Alkyne-acid 15 (0.12, 0.09, 0.06 M) and gold cavitand
2 (0.0048 M) were mixed in chloroform and monitored for up to 24 hours at 55 °C.
kobs reported in s-1, r Error as the root mean square between the fit and raw data
and Turn Over Number at the end of reaction (24 h). aRepeated from Table 3.
Conclusions
We have demonstrated that Au-cavitands possess catalytic ability
in the cyclization of γ-alkynoic acids. Unlike prior published results
with traditional AuCl catalysts, Cavitand 2 interacts with “spectator”
groups. When t-butyl esters were compared to methyl ester
analogs, there was a decrease in conversion, which we haven’t
fully explored. Work also remains to confirm the exact role of
solvent as several different competitions could exist depending on
substrate and product. Benzyl and propenylbenzene groups,
despite their moderate size, slowed reactivity when compared to
larger groups and a detailed kinetic analysis reveals information
about both rate and TON. At decreasing concentrations of 15, ꢌobs
increases and when product 20 is used to spike reactions,
evidence of inhibition exists. The product is capable of inhibiting
the catalyst based on R’ group and perhaps too this R’ group
results in substrate inhibition at high substrate concentration. To
deeper understand this picture we recognize a broader rate
equation will be necessary that will allow us to explore both the
role of substrate and product binding with catalyst 2 (Equation 5).
Substrate
0.12 M 15a
0.09 M 15
0.06 M 15
kobs (s-1)
r Error
TON
17.7 a
11.5
7.7
5.59E-05 a
5.86E-05
6.50E-05
9.69E-07 a
1.69E-06
2.19E-06
The increasing kobs as well as non-overlapping time shifted kinetic
traces can be evidence for either catalyst degradation or product
inhibition. Catalyst degradation seems unlikely in this case: A) the
catalyst can complete 24.5 out of 25 cycles with other substrates
(Table 3), B) the catalyst remains unchanged by 1H NMR analysis
at the end of the cycle, C) no conceivable covalent modification
of catalyst exists.
Finally, we did a series of initial competition experiments to probe
why 15 displays significantly slower kinetics (Scheme 5). First, we
directly compared 15 and 16 by mixing them together and
subjecting them to 4 mol % 2. We immediately noted that the rates
of these two substrates seemed to mimic each other at the 1 hour
time point and were similar after 24 hours. These were similar to
the non-competition results (Table 2). Unsatisfied, we prepared
the lactone 20, the cyclization product 15 and then doped
reactions of substrate 15 and 16. Upon reaction with 2, a stark
decrease in conversion was noted. After 24 hours, only 11% of
substrate 15 was converted into 20 (typically 67%, Table 2). Next,
k3
k1
k2
[A•cat]
[P•cat]
A + cat
P
k-3
k-1
(equation 5)
Gold catalysis already is an intricate process when intramolecular
reactions are involved, indeed activation of alkyne, ring closing,
deprotonation and protonation of gold must occur.47 In addition to
a broader exploration of substrate and product concentrations to
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10.1002/ejoc.201900829
European Journal of Organic Chemistry
COMMUNICATION
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The project described was supported by the generous support of
the National Science Foundation (NSF RUI CHE-1708937). NMR
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10.1002/ejoc.201900829
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Au-Cavitands place a reactive metal
center inwardly directed to a well-
studied binding pocket. The metal
center retains its reactivity, what role
does the pocket play? Specific sized
groups that are known guests for
cavitands slow the reaction progress
of the lactonization of alkynoic acids.
Initial kinetic treatment hints of
substrate and product inhibition for
select R groups.
Supramolecular Catalysis*
Author(s), Corresponding Author(s)*
Page No. – Page No.
O
R
O
O
O
Cl
O
R
4 mol% 2
Au
N
N
HO
O
R'
O
N
N
(H3C)2
N
P
R'
N
O
CHCl3 70 °C
N
O
O
O
O
O
Title
O
O
2:
6 examples, 77-99% conversion
2 examples, 36%, 67%
C11
C11
C11
C11
R' =
C8H17
4 hrs
99%
24 hrs
24 hrs
94%
24 hrs
81%
poor cavitand guests
24 hrs
36%
known cavitand guests
24 hrs
67%
83%
FAST
s
l
o
w
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