Reaction Progress Kinetics Analysis of 1,3-Disiloxanediols as Hydrogen-Bonding Catalysts

Article abstract of DOI:10.1021/acs.joc.7b00875

1,3-Disiloxanediols are effective hydrogen-bonding catalysts that exhibit enhanced activity relative to silanediols and triarylsilanols. The catalytic activity for a series of 1,3-disiloxanediols, including naphthyl-substituted and unsymmetrical siloxanes, has been quantified and compared relative to other silanol and thiourea catalysts using the Friedel Crafts addition of indole to trans-β-nitrostyrene. An in-depth kinetic study using reaction progress kinetic analysis (RPKA) has been performed to probe the catalyst behavior of 1,3-disiloxanediols. The data confirm that the disiloxanediol-catalyzed addition reaction is first order in catalyst over all concentrations studied with no evidence of catalyst self-association. 1,3-Disiloxanediols proved to be robust and recoverable catalysts with no deactivation under reaction conditions. No product inhibition is observed, and competitive binding studies with nitro-containing additives suggest that 1,3-disiloxanediols bind weakly to nitro groups but are strongly activating for catalysis.

Full text of DOI:10.1021/acs.joc.7b00875

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Article
Reaction Progress Kinetics Analysis of 1,3-
Disiloxanediols as Hydrogen-bonding Catalysts
Kayla M Diemoz, Jason E Hein, Sean O Wilson, James C. Fettinger, and Annaliese K. Franz
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 31 May 2017
Downloaded from http://pubs.acs.org on May 31, 2017
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Reaction Progress Kinetics Analysis of 1,3-Disiloxanediols as Hydrogen-bonding Catalysts
Kayla M. Diemoz, Jason E. Hein, Sean O. Wilson, James C. Fettinger, Annaliese K. Franz*
Department of Chemistry, One Shields Avenue, University of California, Davis CA, 95616
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ABSTRACT: 1,3-Disiloxanediols are effective hydrogen-bonding catalysts that exhibit enhanced activity
relative to silanediols and triarylsilanols. The catalytic activity for a series of 1,3-disiloxanediols,
including naphthyl-substituted and unsymmetrical siloxanes, has been quantified and compared relative to
other silanol and thiourea catalysts using the Michael addition of indole to trans-β-nitrostyrene. An in-
depth kinetic study using reaction progress kinetic analysis (RPKA) has been performed to probe the
catalyst behavior of 1,3-disiloxanediols. The data confirms that the disiloxanediol-catalyzed Michael
addition reaction is first order in catalyst over all concentrations studied with no evidence of catalyst self-
association. 1,3-Disiloxanediols proved to be robust and recoverable catalysts with no deactivation under
reaction conditions. No product inhibition is observed and competitive binding studies with nitro-
containing additives suggest that 1,3-disiloxanediols bind weakly to nitro groups but are strongly
activating for catalysis.
INTRODUCTION
In the growing field of organcatalysis,1,2 mechanistic studies can provide valuable insight to evaluate
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catalyst behavior and guide catalyst design.3, ,5, In particular, kinetic profiles of organocatalysts provide
insight to improve activity and selectivity. Recently, the use of reaction progress kinetic analysis (RPKA)
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has gained more wide-spread application because this method can be used to probe a reaction at
synthetically relevant conditions.5,7 Recent reports for hydrogen-bonding and anion-binding catalysts,
such as thioureas (Figure 1), indicate that the formation of higher-ordered species can have a significant
effect on the activity and selectivity of a reaction.8 Examples of both beneficial cooperative catalyst
activation5e, 5g and counterproductive catalyst aggregation have been reported.5f, 9
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As part of a growing interest in hydrogen-bonding catalysis, we and others have demonstrated
opportunities for designing new organocatalysts containing silanol functionalities10 (e.g. silanediols 2),
including a recent report demonstrating that 1,3-disiloxanediols can serve as a new class of anion-binding
catalysts (Figure 1).11 1,3-Disiloxanediols, which contain a siloxane-linked 1,3-arrangement of two
silanols, may offer advantages for catalysis compared to silanediols and other organocatalysts due to their
enhanced solubility, acidity and stability.12 Previous reports of 1,3-disiloxanediols include studies of
anion-binding properties,13 supramolecuclar assembly,14 and applications as organometallic ligands.15 In
the context of catalysis, several modes of intermolecular hydrogen-bonding are available for 1,3-
disiloxanediols that may either lead to cooperative activation or counterproductive catalyst aggregation.16
In the solid state, 1,3-disiloxanediols are known to self-assemble into higher-ordered species via
intermolecular H-bonding.17 In solution, 1H NMR diffusion-ordered spectroscopy (DOSY) studies have
indicated that 1,3-disiloxanediols have the ability to self-associate at high concentrations (i.e. 0.4 M).11
thiourea
silanediol
1,3-disiloxanediol
CF3
CF3
R
Ar
Ar
Ar
S
O
Si
Ar Si
Si
OH
R
OH
HO
F3C
N
H
N
H
CF3
OH
1a
2
3
Franz, 2011
Franz, 2016
Schreiner, 2002
Mattson, 2011
this work
Figure 1. Examples of hydrogen-bonding catalysts evaluated in this study.
Based on the recent activity we reported for 1,3-disiloxanediols as anion-binding catalysts,11 we
envisioned a rigorous mechanistic study to evaluate the behavior of 1,3-disiloxanediols as hydrogen-
bonding catalysts. Here we report the catalytic ability of 1,3-disiloxanediols as hydrogen-bonding
catalysts and reaction progress kinetic analysis (RPKA) for the addition of indole to nitroolefins. The
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addition of indole to nitrostyrene provides a valuable reference reaction because this reaction can be
catalyzed by various organocatalysts,18 including organic silanediols.10c, 10e It is generally accepted that the
rate-limiting step for the indole addition to nitroalkenes and other Michael reactions is carbon-carbon
bond formation. Mechanistic studies of the addition of nucleophiles to nitroolefins catalyzed by
hydrogen-bonding catalysts have primarily utilized computational studies,19 but recently several kinetic
studies have also been reported.4e, 4f, 5f In our study, RPKA has been used to study hydrogen-bonding
activation by 1,3-disiloxanediols over a large range of concentrations (0.05 – 0.3 M) to profile the kinetics
of these hydrogen-bonding catalysts and determine if catalyst self-association either reduces or enhances
activity.20
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RESULTS AND DISCUSSION
Initial studies were performed using 1,1,3,3-tetraphenyldisiloxane-1,3-diol (3a) as a simple
disiloxanediol variant to catalyze the addition of indole (9a) to trans-β-nitrostyrene (8a). Using 20 mol %
of disiloxanediol 3a in DCM demonstrates catalytic activity with Michael adduct 10a produced in 78%
yield based on 1H NMR spectroscopy (Table 1, entry 1 vs 5% yield without catalyst). Solvent
optimization identified o-dichlorobenzene (DCB) as an optimal solvent that increased the yield to 96%
(entry 2 vs 20% yield without catalyst). Decreasing the catalyst loading to 10 and 5 mol %, afforded
yields of 71% and 47% (based on NMR), respectively (entries 3 and 4). The disiloxanediol catalyst can be
recovered from the reaction mixture in high purity with >90% mass recovery (see SI).
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Table 1. Silanol catalysts for Michael addition reactiona
5
NH
catalyst
NO2
6
7
8
N
H
o-dichlorobenzene,
NO2
23 ˚C
9
8a
9a
10a
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Ar
Ar
Ph
O
Ph
Ph Ph
Si
Ph OH
Si
Si
Si
HO OH
HO
OH
Ph Ph
2a: Ar = Ph
2b: Ar = 1-naphthyl
2c: Ar = 4-fluoro-1-naphthyl
3a
4
HO
Ph
O
Ph
Ph
Ph
O
OH
Si
Si
Ph
Ph
Ph
O
Si
O
Si
Si
Ph
Si
Ph
O
O
Ph
OH
Ph
OH Me
Si
Si
SiMe3
HO
O
Ph
OH
5
6
7
entry catalystb mol % time (h) yieldc (%)
1d
3a
20
24
78
96 (95)e
71
2
3
4
3a
3a
3a
20
10
5
24
24
60
47
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8
2a
2b
2c
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20
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24
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24
48
24
24
24
38
38
49
38
21
31
96
86
9
10
11f
12f
7
3a
aAll reactions run with [8a] = 1.9 M. bThe background reaction
(at 24 h) affords 5% yield in DCM, 20% yield in o-dichlorobenzene,
and 32% yield when run without solvent. cYields determined using
1H NMR spectroscopy with PhSiMe3 as internal standard, unless
otherwise indicated. dReaction run in DCM. eIsolated yield after
column chromatography. fReaction performed without solvent.
We proceeded to compare the H-bonding activation of 1,3-disiloxanediols to other silanols. 1,3-
Disiloxanediols demonstrate enhanced catalytic activity as hydrogen-bonding catalysts relative to
silanediols (2a-c) and other silanol derivatives (4-7).21,22 Silanediols 2a-c23 afford significantly lower
yields (38%, 38%, and 49%, respectively) at 20 mol % catalyst loading (Table 1, entries 5-7). A reduced
yield (38%) was also observed using 20 mol % of triphenylsilanol 4 (entry 8). We synthesized and
investigated siloxanols 5 and 6 that retain the 1,1,3,3-tetraphenyldisiloxane motif with one hydroxyl
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group while either replacing the other hydroxyl group with a methyl group or protecting the hydroxy
group as a silyl ether. Both siloxanols 5 and 6 afforded only low yield of product (entries 9 and 10). The
enhanced catalytic activity observed for 1,3-disiloxanediols compared with other organosilanols suggests
that either the self association or the 1,3-diol arrangement is an important structural feature to enhance
silanol acidity for catalysis (e.g. via supramolecular or intramolecular hydrogen bonding).12
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Cis-tetraphenylsiloxane-tetra-ol (7) was also evaluated as a hydrogen-bonding catalyst based on the
potential for intramolecular hydrogen-bonding to enhance catalytic activity.24 We hypothesized that the
more rigid cyclic motif with an all-cis relationship of hydroxyl groups would provide a platform for
intramolecular hydrogen-bonding and exhibit enhanced catalytic activity; however, the limited solubility
of siloxanol 7 in solvents such as DCM, diethyl ether, acetonitrile and DCB precluded our ability to
directly compare the activity of this catalyst with silanols 2-4. When siloxanol 7 was investigated in the
absence of solvent (i.e. neat) at 20 mol % catalyst loading, 96% conversion was observed for the indole
addition reaction, compared to 86% for disiloxanediol 3a (Table 1, entry 11 and 12). The increased
catalytic activity of siloxanol 7 compared to silanediol 3a suggests that intramolecular hydrogen-bonding
may contribute to catalytic activity however the limited solubility precluded our ability to study this
catalyst in more detail.
Next we proceeded to examine the activity for a series of 1,3-disiloxanediols containing electron-
withdrawing groups and/or unsymmetrical siloxanes (Table 2). Switching from phenyl variant 3a (Table
2, entries 1 and 2) to 1,1,3,3-tetra(naphthalen-1-yl)disiloxane-1,3-diol (3b) afforded 99% yield by 1H
NMR spectroscopy with 20 mol % catalyst loading and 81% with 10 mol % catalyst loading (entries 3
and 4). Disiloxanediols 3c and 3d containing alkyl groups maintained good catalytic activity at 10 mol %
(entries 5 and 6), which demonstrates potential for application to chiral disiloxanediol scaffolds. The
catalytic activity of 1,3-disiloxanediols is further enhanced when a fluorine substituent is incorporated in
the unsymmetrical 1,1-bis(4-fluoronaphthalen-1-yl)-3,3-diphenyldi-siloxane-1,3-diol (3e). Catalyst 3e
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afforded the desired product in 91% yield with 10 mol % catalyst loading (entry 7) and moderate activity
was maintained at 5 mol % catalyst loading (entry 8).
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8
Table 2. Comparing 1,3-disiloxanediol catalystsa
9
R1
R2
O
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Si
Si
HO
OH
R1 R2
NH
3a: R1 = Ph, R2 = Ph
3b: R1 = Np, R2 = Np
3c: R1 = i-Pr, R2 = Np
3d: R1 = i-Pr, R2 = NpF
3e: R1 = Ph, R2 = NpF
Np = 1-naphthyl
N
H
3 (xx mol %)
9a
8a
DCB, 23 ˚C
NO2
NO2
Ph
Ph
10a
NpF = 4-fluoro-1-naphthyl
entry catalyst mol % yieldb (%)
1
2
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5
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8
3a
3a
3b
3b
3c
3d
3e
3e
20
10
20
10
10
10
10
5
96 (95)c
71
99 (96)c
81
61
68
91 (97)c
50
aReaction run at 1.88 M. bYield determined using 1H NMR
spectroscopy with PhSiMe3 as an internal standard. cIsolated
yield after column chromatography.
The trends in catalyst activity based on substituent effects and across different classes of catalysts
were quantified using 19F NMR spectroscopy to compare the rates of the Michael addition using 4-
trifluoromethyl-trans-β-nitrostyrene (8b). 1H and 2H NMR kinetics have been previously performed on
this reaction with different hydrogen-bonding catalyst systems.25,21 The 19F NMR spectra are useful for
kinetic measurements because only peaks for the starting material 8b, internal standard (fluorobenzene)
and product 10b are visible, allowing a variety of catalysts to be studied without any peak overlap (Figure
2).
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10b
4
time%=%24%h
5
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8
NO2
catalyst
(10 mol %)
Me
N
F3C
8b
9b
NO2
9
CD2Cl2,
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F3C
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N
10b
Me
8b
time%=%0%h%
Figure 2. 19F NMR reaction monitoring of the addition
of N-methylindole (9b) to 4-trifluoromethyl-trans-
β-nitrostyrene (8b).
The rate of consumption of 4-trifluoromethyl-trans-β-nitrostyrene (8b) was monitored for various
silanol catalysts and compared to the background rate of the reaction (Figure 3). Exponential decay was
observed for 4-trifluoromethyl-trans-β-nitrostyrene (8b) allowing relative rates to be calculated based on
the natural log of the concentration of 8b (see SI). Triphenylsilanol (4) is a very weak catalyst, with a
relative rate of 1.6 with respect to the background reaction. Silanediol 2c exhibits improved activity with
a relative rate of 6.1. 1,3-disiloxanediols exhibit the highest catalytic activity for all classes of silanols
studied, consistent with the yields reported in Tables 1 and 2. The relative rate of reaction with phenyl-
substituted disiloxanediol 3a is 16, and naphthyl-substituted catalyst 3b proceeds with a relative rate of
21. Unsymmetrical disiloxanediol 3d containing alkyl groups proceeds with a relative rate of 11. The
largest rate enhancement was observed upon incorporation of the electron-withdrawing substituent in
disiloxanediol 3e, with a relative rate of 33 compared to the background reaction.
The catalytic activity of 1,3-disilxoanediols was also compared with thioureas, which are a widely
utilized class of organocatalysts.26 Using a phenyl-substituted thiourea such as 1b in the Michael reaction
the rate of consumption of 4-trifluoromethyl-trans-β-nitrostyrene (8b) was only marginally accelerated,
(relative rate of 0.5) compared to phenyl-substituted disiloxanediol 3a which has a much greater rate
enhancement (relative rate of 16). Using thiourea 1a, which incorporates electron-withdrawing
substituents, was observed to accelerate the reaction with a relative rate of 11, albeit at a lower reaction
concentration due to reduced solubility. This data demonstrates that 1,3-disiloxanediols can perform
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similarly, or better, compared to thioureas as hydrogen-bonding catalyts, and offer advantages with
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respect to solubility.
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Figure 3. Comparing relative rates for Michael reaction of 8b and 9b
with silanol catalysts and select thioureas; 10 mol % catalyst loading.
[8b] = 2.0 M and [9b] = 3.0 M for all reactions (except with catalyst
1a as indicated).
Next we performed reaction progress kinetic analysis (RPKA) to study the behavior of 1,3-
disiloxandiols as catalysts using 19F NMR spectroscopy for in-situ reaction monitoring. Following RPKA
protocol, a series of "different excess"experiments were carried out to determine the order of reagents in
the Michael addition reaction.7a First, a series of three experiments were performed using nitrostyrene 8b
and N-methylindole (9b) with catalyst 3a, where only the initial concentration of 8b was varied. Both the
consumption of 4-trifluoromethyl-trans-β-nitrostyrene (8b) and formation of product 10b were monitored
over the entire course of the reaction. Plotting the rate of reaction as a function of the concentration of 8b
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provides the graphical rate law (Figure 4A).27 Excellent overlay was observed for these three trials,
indicating that the reaction rate is directly correlated to the concentration of nitrostyrene 8b. Furthermore,
these experiments imply that the rate of reaction is insensitive to the initial concentration of N-
methylindole (9b), indicating that the reaction is first order in nitrostyrene and zero order in N-
methylindole. Similar conclusions can be drawn when the data is graphed as a function of N-methylindole
9b (see SI).
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A)
B)
C)
2.5
2
30
20
10
0
40
[9b].=.1.5.M.
[9b].=.1.2.M
[9b].=.1.1.M
30
20
10
0
1.5
1
[9b].=.2.25.M
[9b].=.2.0.M
[9b].=.1.8.M
[8b].=.1.5.M
[8b].=.1.2.M
[8b].=.1.1.M
0.5
0
0
0.5
1
1.5
0
0.5
1
1.5
0
500
1000
![9b]0"t
1500
[8b].(M)
[8b].(M)
Figure 4. A) RPKA plot showing rate as a function of nitrostyrene 8b with varying [8b]0. [9b]0 = 2.25 M
and catalyst [3a]0 = 0.15 M for all experiments. B) rate as a function of nitrostyrene 8b with varying N-
methylindole [9b]0. [8b]0 = 1.2 M and catalyst [3a]0 = 0.15 M for all experiments. C) Variable time
normalization analysis (VTNA) showing concentration of nitrostyrene as a function of time with varying
N-methylindole [9b]0. [8b]0 = 1.2 M and catalyst [3a]0 = 0.15 M for all experiments.
The reciprocal experiments were conducted, where the initial concentration of N-methylindole (9b)
was varied (Figure 4B). Again, the rate of reaction correlates well with the concentration of nitrostyrene,
regardless of the change in the initial concentration of N-methylindole. This series confirms that the
reaction rate is insensitive to 9b and instead is entirely controlled by the nitrostyrene. Together these two
sets of experiments confirm that the reaction is first order in nitrostyrene 8b and zero order in N-
methylindole. Similar conclusions were found when a variable time normalization analysis was
performed using data from the “different excess” experiments (see Supporting Information).28 This kinetic
analysis method allows for the determination of order of components in a reaction by utilizing a
normalized time scale to compare concentration profiles. As this method does not depend on the
calculation of the reaction rate it provides information directly from the 19F NMR spectroscopy data.
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The observation that the nucleophile in the reaction is zero order prompted us to study the reaction
under a wider variety of conditions. Once again three experiments were performed where the initial
concentration of N-methylindole 9b was varied. This series includes examples where N-methylindole was
both held as the limiting reagent and present in excess. A variable time normalization analysis was
performed on this data and it can be observed that for this broad set of different conditions, the rate of the
reaction is still insensitive to the concentration of N-methylindole 9b (Figure 4C). This experiment further
supports that the reaction is zero order in indole under a variety of conditions.
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The robustness of 1,3-disiloxanediols as catalysts was also investigated by performing a set of "same
excess"experiments (Figure 5).7a In this series, the concentration difference between nitrostyrene 8b and
N-methylindole (9b) was maintained. While reducing the initial concentration of the nitrostyrene
predictably results in a slower initial rate of reaction, adjusting the reaction time of the progress curves
results in an excellent superposition. Thus, catalyst 3a shows no deactivation over the course of the
reaction and is not inhibited by product 10b. This demonstrates that disiloxanediols are highly robust and
effective catalysts in H-bond activated catalytic manifolds.
Figure 5. Concentration of nitrostyrene 8b as a function of
time for same excess conditions.
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Further kinetic studies were employed paying particular attention to possible catalyst self-association.
As 1,3-disiloxanediols display a strong propensity to undergo self-association via hydrogen bonding11
there is a possibility that higher-ordered species may play a role in the activation of nitrostyrene. This
could take the form of off-cycle complexation, effectively reducing the concentration of the active
catalyst and suppressing the rate of reaction.5g Conversely, self-assembly into higher-ordered species may
generate a more active catalytic species, resulting in reaction acceleration. In either case, if self-
association plays a significant role we would expect to observe a non-linear correlation between the
reaction rate and the initial catalyst concentration.
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The rate of consumption of 4-trifluoromethyl-trans-β-nitrostyrene (8b) was studied over a wide range
of catalyst concentrations (0.025 M – 0.30 M). By plotting the reaction progress against a normalized
time scale, the order of catalyst could be determined across all concentrations studied (Figure 6).29 The
best overlap between the concentration profiles was observed when an exponent of “1” was used,
indicating the reaction is first order in disiloxanediol over all concentrations studies. A similar finding can
be derived by plotting the apparent first order rate constant as a function of the catalyst concentration.30
This analysis shows that the rate of reaction is linearly proportional to the concentration of catalyst over a
wide range (See Supporting Information). Although some deviation from linearity may be present at high
concentration of 3a, this observation is attributed to issues with catalyst solubility at higher
concentrations.31
1.2
[3a] = 0.025 M
[3a] = 0.050 M
[3a] = 0.075 M
1.0
[3a] = 0.20 M
[3a] = 0.25 M
[3a] = 0.30 M
0.8
0.6
0.4
0.2
0.0
0
20
40
60
80
100
ꢀme x [3a]1
Figure 6. Monitoring the consumption of 8b over a range of
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catalyst concentrations. [8b] = 1.0 M and [9b] = 2.25 M for
all reactions. Concentration profiles overlap with an exponent
of 1 to demonstrate first order in catalyst.
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The combination of these kinetic experiments indicate that the monomeric form of the disiloxanediol
is likely the active catalytic species at relevant concentrations (0.025 M – 0.3 M).32 Although this study
does not explicitly rule out the formation of a higher-ordered species, it does confirm that such species
either do not play a significant role in the activation of the nitrostyrene electrophile, or that the
concentration of the dimeric complex is not sensitive to the initial catalyst loading for the range of
concentrations in 3a examined.
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We also explored the potential that catalytically-active aggregates of nitrostyrene and disiloxanediols
can form under reaction conditions. Recent reports from Moran and coworkers have demonstrated that
weak hydrogen-bond acceptors, such as nitro-containing compounds, can serve as a cocatalyst upon
formation of hydrogen-bond aggregates with Brønsted acids.33 To evaluate this possibility for the
disiloxanediol-catalyzed Michael addition reaction, reactions were conducted with either 0.5 or 1.0
equivalents of nitrobenzene (11) to determine if competitive binding or rate acceleration was observed
(Figure 7). The rate of consumption of nitrostyrene 8b (Krel = 16) is not affected by the addition of 0.5
equivalent of nitrobenzene and only displays a minor suppression with 1.0 equivalent (Krel = 13). These
data indicate that nitro-containing compounds do not form catalytically active aggregates with 1,3-
disiloxanediols and instead can act as a minor competitive binder compared with nitrostyrene 8b due to
the weak binding of silanols to nitro-containing molecules. The evidence that the binding interaction of
1,3-disiloxanediol 3a with nitro-containing molecules is a weak interaction is provided by needing to add
a full equivalent of nitrobenzene before even a small rate suppression was observed. While both the
nitrobenzene and the nitrostyrene have weak binding interaction with 1,3-disiloxanediols, only the
binding to the nitrostyrene elecrophile is a productive interaction leading to product formation. The weak
binding of 1,3-disiloxanediols to nitro-containing molecules is further supported by “same excess”
experiments where no product inhibition was observed. Considered together, the small rate suppression
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using a full equivalent of nitrobenzene and no evidence of any product inhibition confirms that 1,3-
disiloxanediols bind weakly to nitro-containing compounds, but can be sufficiently activating to promote
nucleophilic addition to the nitrostyrene.
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Figure 7. Effect of nitrobenzene on the reaction rate: green (Δ) = no
nitrobenzene, purple (¡) = 0.5 equiv, blue (o) = 1.0 equiv. [8b] = 2.0 M,
[9b] = 3.0 M for all experiments.
We have considered several possible modes of hydrogen bonding between 1,3-disiloxanediol
catalysts and electrophiles such as nitrostyrene 8b (Figure 8). Although there is precedent for self-
association of 1,3-disilxoanediols both in the solid state based on x-ray crystallography17 and at high
concentrations in solution based on 1H NMR DOSY experiments,11 these concentrations are higher than
what is relevant for catalytic activity. Moreover, kinetic data suggest that self-association into dimeric or
higher-ordered species (e.g. 14) does not account for activation of the nitrostyrene. Rather, the 1,3-
disiloxanediol is likely acting as a monomer to activate the nitrostyrene in our system. As the monomer,
we envision that activation can either occur via complex 12 with dual hydrogen bonding, or complex 13
with intramolecular hydrogen bonding cooperativity34 (Figure 8). Computational data suggest that
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intramolecular hydrogen bonding is possible for 1,3-disiloxanediols12 and this is further supported by the
kinetic studies presented here, which indicate a monomeric catalyst species.
3
4
5
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7
8
9
Ph
δ–
O
O
H
Ph
Ph
Si
Ph
Ph
δ–
O
O
N
O
Ph
H
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11
12
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Ph
Ar
Si
O
H
Si
O
Si
O
δ–
H
O
N
Ph
Ar
12
O
H
O
δ–
Self-association
OH
or
Si Ph
Ph
Ph Si
Ph
O
Ph
Si
Ph
Ph
O
14
Si
O
Ph
O
H
Catalyst association not
observed at catalytically
relevant condtions
O
Ar
N
H
13
O
Figure 8. Proposed modes of hydrogen bonding activation of nitrostyrene.
1H NMR spectroscopy was used to further study the binding interaction of 1,3-disiloxanediol 3a with
nitrostyrene. Previously 1,3-disiloxanediols have demonstrated binding interactions with both anionic
Lewis bases such as chloride ions13 and neutral Lewis bases such as DMF.11 Upon titration of five
equivalents of nitrostyrene, small shifts (e.g. 0.1 ppm) for the silanol peak were observed in the 1H NMR
spectra indicating a binding interaction (see SI). The small shift observed with nitrostyrene prevented
binding constants from being accurately calculated, however indicates a weak binding interaction
compared to chloride ions and DMF (e.g. where 1H NMR shifts up to 3.79 ppm are observed). The weak
interaction observed by 1H NMR spectroscopy between 1,3-disiloxanediol 3a with nitrostyrene indicate
that 1,3-disiloxanediols are weakly binding to nitro groups, but can be strongly activating.
In order to gain more insight about inter- and intramolecular hydrogen-bonding patterns of 1,3-
disiloxanediols, both 3b and 3d were crystallized and X-ray structures were obtained. Previous solid-state
studies with silanediols have provided insight into hydrogen-bonding interactions that are relevant for
catalysis.10a, 10c For disiloxanediol 3b a linear intermolecular hydrogen bond polymeric network is
observed where each molecule acts as both a hydrogen-bond donor and acceptor (Figure 9A). This
uncommon hydrogen-bonding pattern is attributed to the steric demand of the naphthyl substituents that
prevents head-to-head hydrogen-bonding that is traditionally observed with 1,3-disiloxanediols.16 In
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contrast, for disiloxanediol 3d discrete intermolecular hydrogen-bonded dimeric clusters are observed in
the solid state rather than intermolecular polymeric hydrogen-bond networks (Figure 9B). The dimeric
pattern observed in solid state for 3d shows interesting hydrogen-bonding with H3 having two one-half
occupancy positions (H3A and H3B). One occupancy position has an intermolecular hydrogen bond to
O3 [1.946 Å] in the partner dimeric molecule while the other occupancy position has a unique H-bonding
interaction with the fluorine [2.214 Å] of the naphthyl group in the adjacent dimeric cluster. Though the
solid-state structures may not reflect the solution state, the fact that there is no evidence of intramolecular
hydrogen-bonding observed in either crystal structure may still provide insight to the mode of H-bonding
for catalysis. These structures suggest that an intramolecular hydrogen-bonding activation i.e. 13, may not
be favored. Further solution state studies are being conducted to provide further evidence for the binding
mode of 1,3-disiloxanediols.35
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A
B
F4AA
F14B
H3BB
Si2B
H1AA
O2B
Si1B
O3B
O1AA
H3AA
Si1C
O3AA
O1B
H1B
O2AA
Si2C
H3BC
F4
F14C
F14A
F4B
O1
Si2A
O2A
H3BA
H1
O3A
H3A
Si1A
Si1
O1A
H1A
O2
O3
Si2
H3B
F14
F4A
Figure 9. X-Ray structures of 1,3-disiloxanediols 3b (A) and 3d (B).
1,3-disiloxanediol 3b forms a linear polymeric hydrogen-bonded network
and 3d forms a dimeric cluster. Selected bond lengths for 3b (bond lengths
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in Å): H⋅⋅⋅O 1.899. Selected bond lengths for 3d (bond lengths in Å):
O(1)-H(1)...O(3) 2.203; O(3)-H(3A)...O(3) 1.946; O(3)-H(3B)...F(4) 2.214.
6
7
8
9
A catalytic cycle is proposed based on the kinetic data (Figure 10).36 In the first step, a monomeric
disiloxanediol activates the nitrostyrene through hydrogen bonding. While two modes of activation are
possible for a monomeric disiloxanediol catalyst, current results suggest that dual activation (e.g. complex
12) may be predominant due to lack of cooperative intramolecular hydrogen-bonding observed in the
solid state analysis of 3b and 3d. As the reaction was determined to be first order in 4-trifluoromethyl-
trans-β-nitrostyrene (8b), binding to form an activated complex, i.e. 12 is rate limiting. This is consistent
with the observation that the reaction is not affected by competitive binding to nitrobenzene, indicating
that the disiloxanediols are weakly binding but strongly activating. As the pre-equilibrium is shifted far in
favour of the free catalyst 3a, nucleophilic addition of N-methylindole to the activated complex (12) is
rapid, giving the observed zero order behavior in 9b to yield adduct 15. Finally, proton transfer affords
product 10b. No product inhibition was observed, further confirming that that disiloxanediols bind
weakly to nitro groups, which facilitates catalyst turnover.
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Me
Catalyst Resting
State
N
Ph
Ph
O
Ph
Ph
NO2
Si
OH
Si
OH
Ar
Ar
NO2
8b
10b
3a
turnover-limiting
step
Ph
Si
Ph
O
Me
Ph
N
O
Ph
O
δ–
O
H
H
Si
Ph
O
N
Si
O
O
Ph
H
N
Ar
Si
Ph
O
O
H
O
Ar
δ–
Ph
15
12
or 13
Me
N
9b
Figure 10. Proposed catalytic cycle based on kinetic data.
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In many previous examples of hydrogen-bonding catalyzed indole additions to nitroalkenes and other
Michael reactions the carbon-carbon bond formation is often the rate determining step.4e, 4f In this reaction
the first order-dependence on nitrostyrene is attributed to the weak binding of the 1,3-disiloxanediol
resulting in a small concentration of activated complex 13. Though the zero-order dependence in 9b could
also be explained by saturation kinetics we do not believe that is the case in this reaction.37 An example of
saturation behavior is the thiourea catalyzed addition of acetylacetone to nitrostyrene, where the catalyst
must deprotonate the acetylacetone in a pre-complex of the rate determining step.4e A pre-complex would
not be observed between N-methylindole 9b and disiloxanediol 3a as it would reduce the nucleophilicity
of N-methylindole and hinder the reaction. This would likely manifest as a negative order in indole, as
such a binding would create an off-cycle reservoir depleting the concentration of active catalyst.
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In conclusion, a detailed kinetic study of 1,3-disiloxanediols as hydrogen-bonding catalysts has been
conducted in order to determine the role of self-association and compare the relative catalytic activity to
other silanols and organocatalysts. Kinetic data quantify the enhanced catalytic ability of 1,3-
disiloxanediols compared to silanediols and triarylsilanols, as well as simple thioureas, due to factors such
as increased acidity, solubility and resistance to self-association at catalytically relevant concentrations.
RPKA suggests that a monomer is the active catalyst species for hydrogen-bonding catalysis over all
reaction concentrations investigated and catalyst self-association does not play a key role in the mode of
activation. Due to weak binding with the nitro group, no product inhibition is observed for the Michael
addition reaction and 1,3-disiloxanediols proved to be robust catalysts with no catalyst decomposition or
loss of activity observed over the course of the reaction. The 1,3-disiloxanediol could also be recovered
after the reaction further demonstrating the robust nature of the catalyst. The enhanced catalytic activity
of 1,3-disiloxanediols presented here provide valuable insight into the hydrogen-bonding abilities and
properties associated with the Si–O bond to guide incorporation of organosilanols for catalyst design.
EXPERIMENTAL SECTION
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General Methods and Materials: All nuclear magnetic resonance (NMR) spectra were obtained on
a Bruker Nanobay AVIIIHD 400 (400 MHz for 1H; 100 MHz for 13C, 376 MHz for 19F) equipped with an
7
8
1
autosampler, and/or a Varian VNMRS 600 (600 MHz for H; 150 MHz for 13C; 119 MHz for 29Si) at
9
room temperature unless noted otherwise. Chemicals shifts were reported in parts per million (δ scale),
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1
and referenced according the following standards: tetramethylsilane internal standard for H signals in
1
CDCl3, benzene residual solvent (δ 7.16) for H signals in benzene, deuterated chloroform, or benzene
carbon resonances (middle peak is δ 77.1 or δ 128.1, respectively) for 13C{1H} signals, tetramethylsilane
external standard in CDCl3 for 29Si{1H} signals, and trifluoromethylbenzene external standard in CDCl3
for 19F(1H) signals. Coupling constants were reported in hertz (Hz) and multiplicities were reported as
follows: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m), broadened (b). Compounds were
analyzed for HRMS on a Thermo Fisher Orbitrap (San Jose, CA) using electrospray in the negative ion
mode at >60,000 resolution and using 5 kV spray voltage, with a curtain plate temperature of 275 °C and
sheath gas setting of 15. These settings result in mass accuracies <5 ppm. Samples were analyzed via flow
injection analysis by injecting 5 µL samples into a stream of 50% acetonitrile and 50% aqueous solution
of 0.1% formic acid, flowing at 200 µL/minute.
Commercially available reagents were purchased and used without further purification unless
otherwise indicated. Triphenylsilanol was prepared in one step using Pd/C hydrolysis of triphenylsilane
and the spectral data was confirmed to match previously reported spectra in literature.10a 4-
trifluoromethyl-trans-β-nitrostyrene was synthesized in one step following literature procedure and
matched previously reported spectra.38 Di(naphthalen-1-yl)silanediol (2b) was synthesized according to
literature procedure using a Pd/C-mediated hydrolysis of di(naphthalen-1-yl)silane.10c 1,1,3,3-
Tetraphenyldisiloxane-1,3-diol was synthesized in one step from 1,3-dichloro-1,1,3,3-
tetraphenyldisiloxane.10a 1,3-Disiloxanediols (1b – 1e) were synthesized according to literature
procedures starting from the addition of the corresponding aryl Grignard to trichlorosilane to
trichlorosilane.11 Cis-tetra[(phenyl)(hydroxyl)]cyclotetrasiloxane (7) was synthesized according to
literature procedure starting from phenyltrimethoxysilane.24
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Reactions were analyzed by thin layer chromatography (TLC) on EMD glass plates that were pre-
coated with silica gel 60 F254, and the reactions were purified by column chromatography using Acros
silica gel 60 Å (0.035-0.070 mm). The following abbreviations are used throughout: Ethyl acetate
(EtOAc), dichloromethane (DCM), triethylamine (Et3N), lithium aluminum hydride (LAH) and 1,2-
dichlorobenzene (o-DCB).
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Synthesis of Bis(4-fluoronaphthalen-1-yl)silane: Magnesium turnings (0.728 g, 29.8 mmol, 2.50 equiv)
were dissolved in 45 mL of Et2O in an Ar-charged 2-neck flask followed by the addition of a few drops of
dibromoethane as an activator. 1-Bromo-4-fluoronaphthalene (5.62 g, 25.0 mmol, 2.10 equiv) was added
to the reaction, heated to reflux and allowed to stir for 3 h. The reaction flask was cooled to –78 °C and
trichlorosilane (1.20 mL, 11.9 mmol, 1.00 equiv) was added. The reaction was allowed to warm to room
temperature and stirred for an addition 12 h. The reaction was then cooled down to –78 °C and then LAH
(4.0 M in Et2O, 3.00 mL, 11.9 mmol, 1.00 equiv) was added dropwise. The reaction was warmed to room
temperature, stirred for an additional 3 h, at which time it was quenched with saturated aq. Rochelle’s salt
(15 mL) and filtered over celite. The organic layer was separated and the aqueous layer was washed with
Et2O (3 x 10 mL), the organic layers were combined and washed with brine (15 mL), dried over
anhydrous MgSO4, filtered, and then concentrated in vacuo. The product was purified by recrystallization
in a hexanes/Et2O mixture to yield the silane as a yellow solid (2.39 g, 84%). 1H NMR (600 MHz, CDCl3)
δ 8.16 (dd, J = 8.0, 1.5 Hz, 2H), 8.05 (dd, J = 8.0, 1.7 Hz, 2H), 7.66 (dd, J = 7.5, 6.0 Hz, 2H), 7.59 – 7.48
(m, 4H), 7.10 (dd, J = 10.6, 7.5 Hz, 2H), 5.49 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 161.0 (d, J1
=
CF
256.1 Hz), 138.9 (d, J4 = 4.5 Hz), 137.0 (d, J3 = 8.4 Hz), 127.7 (d, J4 = 3.1 Hz), 127.4, 126.2 (d,
CF
CF
CF
J4CF = 2.0 Hz), 125.0 (d, J3CF = 4.7 Hz), 123.9 (d, J2CF = 15.3 Hz), 121.3 (d, J3CF = 5.9 Hz), 109.3 (d, J2
= 18.7 Hz); 19F NMR (376 MHz, CDCl3) δ –119.9 (m); 29Si NMR (119 MHz, CDCl3) δ –39.0.
CF
Synthesis of bis(4-fluoronaphthalen-1-yl)silanediol (2c). Pd/C (0.050 g, 0.047 mmol, 0.050 equiv, 10
wt %) was added to a solution of bis(4-fluoronaphthalen-1-yl)silane (0.30 g, 0.94 mmol, 1.0 equiv) in
Et2O (9.3 mL) in a round-bottom flask. Deionized water (0.17 mL, 9.4 mmol, 10 equiv) was added.
Evolution of H2 gas was observed initially and reaction was allowed to stir for 1 h until complete
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consumption of the silane based on TLC. The Pd/C was removed through filter paper and the filtrate was
dried over MgSO4, filtered, and then concentrated in vacuo. The crude product was purified using
column chromatography (4:1 hexanes/EtOAc) to yield silanediol 2c as a white solid (0.28 g, 85%). 1H
NMR (600 MHz, CD2Cl2) δ 8.30 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H), 7.95 (dd, J = 7.6, 6.2 Hz,
2H), 7.53 (ddd, J = 8.4, 6.9, 1.3 Hz, 2H), 7.47 (ddd, J = 8.4, 6.9, 1.3 Hz, 2H), 7.15 (dd, J = 8.4, 7.6 Hz,
2H), 3.53 (s, 2H); 13C NMR (150 MHz, CD2Cl2) δ 160.9 (d, J1 = 255.8 Hz), 138.4 (d, J4 = 4.8 Hz),
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CF
CF
135.9 (d, J3CF = 8.9 Hz), 128.8 (d, J3CF = 5.1 Hz), 128.1 (d, J4CF = 3.4 Hz), 127.3, 126.1 (d, J4CF = 2.1 Hz),
123.7 (d, J2 = 15.3 Hz), 121.0 (d, J3 = 6.5 Hz), 108.8 (d, J2 = 18.8 Hz); 19F NMR (376 MHz,
CF
CF
CF
CD2Cl2) δ –120.1 (m). HRMS (ESI): Exact mass calcd for C20H13F2O2Si [M – H]–, 351.0653. Found
351.0655.
Synthesis of 3-methyl-1,1,3,3-tetraphenyldisiloxan-1-ol (5). Diphenylsilanediol (0.25 g, 1.2 mmol,
1.0equiv) was dissolved in DMF (5 mL) and stirred at room temperature while imidazole (79 mg, 1.2
mmol, 1.0 equiv) was added, followed by the addition of Ph2MeSiCl (0.42 mL, 1.2 mmol, 1 equiv). The
reaction was stirred for 12 h at which point the reaction was quenched by the addition of saturated aq.
NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 5 mL).
The organic layers were combined and washed with brine (5 mL). The organic layer was further dried
over anhydrous MgSO4, filtered, and then concentrated in vacuo. The crude product was purified by flash
column chromatography (SiO2, 2% EtOAc/hexanes to 5% EtOAc/hexanes to 10% EtOAc/hexanes
gradient) to afford silanol 5 (0.23 g, 47%) as a clear, viscous liquid. 1H NMR (600 MHz, CDCl3) δ 7.89 –
7.61 (m, 8H), 7.60 – 7.21 (m, 12H), 3.06 (s, 1H), 0.76 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 137.3,
135.0, 134.5, 134.1, 130.3, 129.9, 128.0, 127.9, -0.5; 29Si NMR (119 MHz, CDCl3) δ –9.1, –36.4. HRMS
(ESI): Exact mass calcd for C25H23O2Si2 [M – H]–, 411.1237. Found 411.1235.
Synthesis of 5,5,5-trimethyl-1,1,3,3-tetraphenyltrisiloxan-1-ol (6). Tetraphenyldisiloxanediol 3a (0.332
g, 0.800 mmols, 1.00 eqiv) was dissolved in DCM (8.0 mL) and stirred at room temperature while
imidazole (0.041 g, 0.60 mmol, 0.75 equiv) was added, followed by the addition of TMSCl (0.76 mL,
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0.60 mmol, 0.75 equiv). The reaction was stirred for 3 h at which point it was quenched by the addition of
saturated aq. NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc
(3 x 5 mL). The organic layers were combined and washed with brine (5 mL). The organic layer was
further dried over anhydrous MgSO4, filtered, and then concentrated in vacuo. The crude product was
purified by flash column chromatography (SiO2, 10% EtOAc/hexanes) to afford silanol 6 (0.079 g, 20%)
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as a clear, viscous liquid. H NMR (600 MHz, CDCl3) δ 7.63 (m, 8H), 7.41 (m, 4H), 7.33 (m, 8H), 2.69
(s, 1 H), 0.04 (s, 9 H); 13C NMR (150 MHz, CDCl3) δ 135.8, 134.9, 134.5, 134.4, 130.3, 130.1, 127.9,
127.9, 1.9. Exact mass calcd for C27H29O3Si3 [M – H]–, 485.1424. Found 485.1395.
General Procedure for Indole Addition to trans-β-Nitrostyrene. A general procedure for the indole
addition to trans-β-nitrostyrene was adapted from previous literature reports (run at a higher
concentration of 1.9 M).3 The catalyst (0.0752 mmol, 0.200 equiv) and trans-β-nitrostyrene (8a) (56 mg,
0.38 mmol, 1.0 equiv) were added to a flame-dried, Ar-purged vial and dissolved in solvent (0.2 mL). To
the reaction mixture was added indole (9a) (66 mg, 0.56 mmol, 1.5 equiv) and the resulting solution was
stirred for 24 h. The reaction was either loaded directly onto silica gel for purification by flash column
chromatography (SiO2, 5% EtOAc/hexanes to 15% EtOAc/hexanes) or the yields were obtained using 1H
NMR spectroscopy with trimethylphenylsilane as an internal standard. To obtain the yield using 1H NMR
spectroscopy, the reaction mixture was concentrated in vacuo at room temperature and 0.6 mL of CDCl3
was added, followed by the addition of 10 µL of trimethylphenylsilane. An aliquot of this mixture was
1
transferred to an NMR tube and the H NMR spectrum was acquired at room temperature with 8 scans.
Integrations for the product and internal standard were compared. The spectra of the products matched the
values reported in literature.10a
Procedure for Catalyst Recovery Experiment: Using 1,3-disiloxanediol 3a, the above general
procedure was followed, using a scale twice as large: catalyst 3a (63 mg, 0.15 mmol, 0.2 equiv),
trans-β-nitrostyrene (8a) (0.10 g, 0.76 mmol, 1.0 equiv), indole (9a) (0.13 g, 1.1 mmol, 1.5
equiv) and 0.4 mL of o-DCB. After the reaction was allowed to run for 24 h, the crude reaction
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mixture was loaded directly onto a silica column. A solvent mixture of hexane/DCM (1:1) was
used to elute any excess starting material and product and then the catalyst was eluted from the
column using ethyl acetate. 1,3-disiloxanediol was recovered in high purity (see SI) in 92% (58
mg).
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General Procedure for monitoring addition of N-methylindole to 4-trifluoromethyl-trans-β-
nitrostyrene using 19F NMR spectroscopy: A stock solution was made with catalyst 3a and a second
stock solution was made containing both fluorobenzene and 4-trifluoromethyl-trans-β-nitrostyrene (8b).
The desired amount of each stock solution and CD2Cl2 were transferred to an oven-dried and argon-
purged NMR tube. An initial 19F NMR spectrum was taken before the addition of N-methylindole (9b)
and then the reaction was monitored by taking a spectrum every 30-60 minutes. 4 scans with a 25 second
relaxation delay were taken to assure complete relaxation for accurate integrations. Fluorobenzene was
used as an internal standard (–113.0 ppm).
Concentration of starting material and product were calculated based off the raw integrals.
Overall first order was observed, kobs were calculated by taking the ln[SM], best fit lines were observed
with high R2 for all catalysts.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the Internet at http://pubs.acs.org.
1H and 13C NMR spectra for all pure products.
AUTHOR INFORMATION
Corresponding Author
Telephone: 530-752-9820. E-mail: akfranz@ucdavis.edu
Notes
The authors declare no competing financial interest.
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REFERENCES
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18. For a recent review of additions of indole to nitroolefins, see: Lancianesi, S.; Palmieri, A.;
Petrini, M. Chem. Rev. 2014, 114, 7108-7149.
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19. For selected examples of computational studies of nucleophilic additions to nitroolefins, see:
(a) Roca-Lopez, D.; Marques-Lopez, E.; Alcaine, A.; Merino, P.; Herrera, R. P. Org. Biomol.
Chem. 2014, 12, 4503-4510; (b) Domingo, L. R.; Perez, P.; Saez, J. A. RSC Adv. 2013, 3, 7520-
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Chem. 2012, 8, 1485-1498.
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20. In the case of silanediols, we have proposed that hydrogen-bonding activation by silanediols
2 (Figure 1) may be enhanced by self association into a hydrogen-bonded dimer, which can
enhance the acidity of the silanol for cooperative activation. X-ray structures provide further
evidence of formation of the hydrogen-bonded dimer and activation of a carbonyl, see references
10a and 10c.
21. The hydrogen-bonding ability of organocatalysts has been quantified using a UV-Vis
method, see: Walvoord, R. R.; Huynh, P. N. H.; Kozlowski, M. C. J. Am. Chem. Soc. 2014, 136,
16055-16065.
22. The acidity of hydrogen-bonding catalysts has been shown to correlate to the rate of this
Michael addition reaction, see: (a) Samet, M.; Kass, S. R. J. Org. Chem. 2015, 80, 7727-7731;
(b) Shokri, A.; Wang, X.-B.; Kass, S. R. J. Am. Chem. Soc. 2013, 135, 9525-9530.
23. Catalyst 2b had limited solubility under reaction conditions, however performing the reaction
neat did not increase catalytic activity.
24. Ito, R.; Kakihana, Y.; Kawakami, Y. Chem. Lett. 2009, 38, 364-365.
25. Fan, Y.; Kass, S. R. Org. Lett. 2016, 18, 188-191.
26. (a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299-4306; (b) Zhang, Z.; Bao, Z.; Xing, H.
Org. Biomol. Chem. 2014, 12, 3151-3162.
27. Rate was calculated from a linear regression on three sequential time points and the negative
slope corresponded to the rate of the middle time point.
28. Burés, J. Angew. Chem., Int. Ed. 2016, 55, 16084-16087.
29. Burés, J. Angew. Chem., Int. Ed. 2016, 55, 2028-2031.
30. Kobs is obtained from the slope of plots of ln[8b] vs. time for a series of different
concentrations of 3a.
31. Reactions with catalyst concentrations above 0.3 M were not possible due to insolubility of
3a.
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32. We also investigated dinaphthylsilanediol 2b in the Michael addition reaction to draw
comparisons with 1,3-disiloxanediols; however, the limited solubility of silanediol 2b only
allowed monitoring catalyst concentrations up to 0.15 M. Data for this concentration range only
indicates first order behavior in catalyst, but we are hesitant to draw conclusions from
experiments based on this concentration range.
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33. Dryzhakov, M.; Hellal, M.; Wolf, E.; Falk, F. C.; Moran, J. J. Am. Chem. Soc. 2015, 137,
9555-9558.
34. For examples of diols that exhibit hydrogen-bonding cooperativity, see: (a) O'Leary, D. J.;
Hickstein, D. D.; Hansen, B. K. V.; Hansen, P. E. J. Org. Chem. 2010, 75, 1331-1342; (b)
Vicente, V.; Martin, J.; Jiménez-Barbero, J.; Chiara, J. L.; Vicent, C. Chem. Eur. J. 2004, 10,
4240-4251; (c) Maes, G.; Smets, J. J. Phys. Chem. 1993, 97, 1818-1825.
35. Low temperature 1H NMR spectroscopy studies were utilized to look for evidence of
intramolecular hydrogen-bonding. In CD2Cl2 temperatures as low as –60 °C were examined and
the hydrogens remained equivalent by NMR which further suggests that intramolecular hydrogen
bonding does not occur.
36. The CF3 substitution on the nitrostyrene is not expected to significantly change the
mechanism of the reaction. Reaction times for substrates with CF3 are comparable to hydrogen
substitution (see Supporting Information).
37. Competition experiments were performed with both N-methylindole and 3-methoxy-N,N-
dimethylaniline present as nucleophiles in the addition to trifluoromethyl-trans-β-nitrostyrene 8b
catalyzed by 3a. Comparable addition of both nucleophiles to nitrostyrene was observed further
supporting the rate of the reaction is not dependent on the nucleophile (see Supporting
Information).
38. Simpson, A. J.; Lam, H. W. Org. Lett. 2013, 15, 2586-2589.
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