Cooperative hydrogen-bonding effects in silanediol catalysis

Article abstract of DOI:10.1021/ol202971m

The importance of cooperative hydrogen-bonding effects and SiOH-acidification is described for silanediol catalysis. NMR binding, X-ray, and computational studies provide support for a unique dimer resulting from silanediol self-recognition. The significa

Full text of DOI:10.1021/ol202971m

ORGANIC
LETTERS
2012
Vol. 14, No. 1
186–189
Cooperative Hydrogen-Bonding
Effects in Silanediol Catalysis
Ngon T. Tran, Sean O. Wilson, and Annaliese K. Franz*
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, United States
akfranz@ucdavis.edu
Received November 4, 2011
ABSTRACT
The importance of cooperative hydrogen-bonding effects and SiOH-acidification is described for silanediol catalysis. NMR binding, X-ray, and
computational studies provide support for a unique dimer resulting from silanediol self-recognition. The significance of this cooperative
hydrogen-bonding is demonstrated using novel fluorinated silanediol catalysts for the addition of indoles and N,N-dimethyl-m-anisidine to
trans-β-nitrostyrene.
The versatile H-bonding capabilities of silanols and silane-
diols offer opportunities to discover new activating groups for
organocatalysis.1,2 Based on structural and NMR binding
studies, silanediols such as 1 are known to bind anions such as
acetate and chloride in a dual H-bonding mode.3 As part of
our program to explore and develop silanediols as a new class
of H-bonding4 catalysts, we recently reported the first example
of silanediol catalysis.5 We have demonstrated that silanediols
bind strongly to neutral carbonyl compounds (e.g. DMF and
benzaldehyde) and can catalyze a DielsꢀAlder reaction.5a
Using computational and mass spectrometry studies, we have
also shown that silanediols are comparable to known organ-
ocatalysts in acidity.5b Silanediols exhibit dual donor and
acceptor properties through which new modes of activation
and cooperative catalysis may be realized. To evaluate the
catalytic activity of silanediols, we designed and synthesized
new stable, isolable, and soluble silanediols 2ꢀ4 with electron-
withdrawing fluoro groups (Figure 1).5 Incorporating a
mesityl group provides a general strategy to overcome pro-
blems related to condensation as well as solubility.
Here, we demonstrate a new class of stable, isolable
silanediols (2ꢀ4) that catalyze the addition of heteroarenes
to trans-β-nitrostyrene. The indole addition to nitrostyrene is
an important CꢀC bond-forming reaction that is known to
be catalyzed by silica gel,6 as well as organocatalysts such as
thioureas and 2-aminopyridinium ions.7 This reaction
provides an excellent system to study the cooperative
H-bonding effects for silanediol catalysts.8 Due to the
self-recognition and cooperative H-bonding capabilities,9
these silanediol catalysts provide exciting opportunities to
(1) For reviews of silanols, see: (a) Chandrasekhar, V.; Boomishankar,
R.; Nagendran, S. Chem. Rev. 2004, 104, 5847–5910. (b) Lickiss, P. D. Adv.
Inorg. Chem. 1995, 42, 147–262. (c) For the first application of organosi-
€
lanols as chiral ligands in asymmetric catalysis, see: Ozc-ubukc-u, S.;
Schmidt, F.; Bolm, C. Org. Lett. 2005, 7, 1407–1409.
(2) For examples describing the synthesis and H-bonding capabilities of
chiral silanediols for the design of protease inhibitors, see: (a) Nielsen, L.;
Skrydstrup, T. J. Am. Chem. Soc. 2008, 130, 13145–13151. (b) Nielsen, L.;
Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup, T. J. Org. Chem.
2007, 72, 10035–10044. (c) Sieburth, S. M.; Chen, C.-A. Eur. J. Org.
Chem. 2006, 311–322. (d) Mutahi, M. W.; Nittoli, T.; Guo, L.; Sieburth,
S. M. J. Am. Chem. Soc. 2002, 124, 7363–7375. (e) Sieburth, S. M.;
Nittoli, T.; Mutahi, A. M.; Guo, L. Angew. Chem., Int. Ed. 1998, 37,
812–814. For an example where the enhanced acidity of silanols can
improve binding to a receptor, see: Daiss, J. O.; Burschka, C.; Mills, J. S.;
Montana, J. G.; Showell, G. A.; Warneck, J. B. H.; Tacke, R. Organo-
metallics 2006, 25, 1188–1198.
(3) Kondo, S.-I.; Harada, T.; Tanaka, R.; Unno, M. Org. Lett. 2006,
8, 4621–4624.
(4) (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–
5743. (b) Connon, S. J. Chem.;Eur. J. 2006, 12, 5419–5427.
(5) (a) Tran, N. T.; Min, T.; Franz, A. K. Chem.;Eur. J. 2011, 17,
9897–9900. (b) Liu, M.; Tran, N. T.; Franz, A. K.; Lee, J. K. J. Org.
Chem. 2011, 76, 7186–7194.
(6) Shumaila, A. M. A.; Kusurkar, R. S. Synth. Commun. 2010, 40,
2935–2940.
r
10.1021/ol202971m
Published on Web 12/07/2011
2011 American Chemical Society

silanediols 1ꢀ4 (Table 1).11,12 With a monosilanol (e.g.,
triphenylsilanol), no catalysis was observed and the reac-
tion yield matches that of the background rate (entries
1ꢀ2). Diphenylsilanediol and aryl silanediols such as 1 and 2
also showed low catalytic activity (entries 3ꢀ5). The
enhanced solubility of silanediol 2 may explain why this
silanediol shows equal or greater catalytic activity com-
pared to the phenyl and naphthyl derivatives, even though
they are calculated to be more acidic.13 Silanediols 3 and 4,
which maintain the mesityl group while also incorporating
electron-withdrawing groups, provided the highest cataly-
tic activity (entries 6ꢀ7). Silica gel is also known to
catalyze this reaction with a high yield (entry 8),6 and this
is attributed to the fact that the silica surface contains
silanols and silanediols that exhibit cooperative H-bonding,
thus providing enhanced activation.14 From these results,
we conclude that the catalytic ability is dependent on the
acidity as well as the solubility of the silanediol, which
dictates the level of association and cooperative
H-bonding.
Figure 1. Silanediol catalysts studied here.
investigate new modes of H-bonding activation that are
distinct from other dual H-bonding organocatalysts
such as thioureas. Here we have investigated the mode
of H-bonding with silanediols 1ꢀ4 and propose that
the primary activation of trans-β-nitrostyrene proceeds
through single-point H-bonding with a unique dimeric
structure in a complex such as 6 (Scheme 1). Our previous
structural and NMR binding studies have demonstrated
that silanediols 2ꢀ4 bind strongly to neutral carbonyls
through single point H-bonding5a activation. While self-
association has been studied for other bifunctional organ-
ocatalysts, in these cases, the formation of a dimer often
blocks the available H-bonding positions, thus reducing
catalytic activity and lowering enantioselectivity.10
Table 1. Indole Additiona
Scheme 1. Monomeric vs Dimeric Active Species
yield in
DCM (%)c
solvent-free
yield (%)
b
entry
catalyst
none
pKa
1
2
3
4
5
6
7
8
ꢀ
10
10
19
33
40
68
92d
91
32
45
52
65c
73
83
92e
78
Ph3SiOH
11.7
11.4
11.8
12.4
11.9
11.6
Ph2Si(OH)2
1
2
3
4
silica gelf
6.8 ( 0.2
a All reactions performed at 2.0 M with 1.5 equiv of indole. b See
ref 13. c Yields are reported as an average of 2ꢀ4 replicates. See the
Supporting Information for a table with standard deviations and
experimental procedures. d The reaction with N-methyl indole proceeds
with 99% yield with catalyst 4. e Reaction run for 4 h. f 20 wt % catalyst
loading, see ref 6.
Initially we investigated the FriedelꢀCrafts addition of
indole to nitrostyrene to compare the catalytic activity of
Because silanediols such as 1ꢀ4 exist in a H-bonded
dimer or polymeric network in the crystalline form,1,5
we hypothesized that a solvent-free reaction would
also proceed efficiently. Thus, the indole addition reaction
was also examined under solvent-free conditions where the
two solid reagents were stirred directly with the silanediol
catalyst. This solvent-free reaction proceeds efficiently,
which indicates the importance of cooperative H-bonding
in the crystalline form, or resulting from concentration
effects, to enhance catalysis.
€
(7) Selected examples: (a) Schneider, J. F.; Falk, F. C.; Frohlich, R.;
Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269. (b) Ganesh, M.; Seidel,
D. J. Am. Chem. Soc. 2008, 130, 16464–16465. (c) Takenaka, N.;
Sarangthem, R. S.; Seerla, S. K. Org. Lett. 2007, 9, 2819–2822. (d) Gu,
Y.; Ogawa, C.; Kobayashi, S. Org. Lett. 2007, 9, 175–178. (e) Berner,
O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877–1894.
(8) While this manuscript was in preparation, the indole addition to
nitrostyrene was reported to be catalyzed by silanediol 1 and Ph3SiOH;
see: Schafer, A. G.; Wieting, J. M.; Mattson, A. E. Org. Lett. 2011, 13,
5228–5231. We cannot reproduce these results with multiple replicates
examined. We attribute the difference in reactivity to the presence of
trace acid (i.e. HCl produced upon hydrolysis of the silyl chloride)
in their synthesis of silanediol 1. Our synthetic route utilizes a silane
precursor to avoid production of HCl. See Supporting Information.
(9) Based on NMR binding experiments, we have calculated self-
association constants for silanediols to be 4.6ꢀ7.7 Mꢀ1. These NMR
studies show that self-association increases significantly with concentra-
tion: see Supporting Information and ref 5a.
(10) (a) Jang, H. B.; Rho, H. S.; Oh, J. S.; Nam, E. H.; Park, S. E.;
Bae, H. Y.; Song, C. E. Org. Biomol. Chem. 2010, 8, 3918–3922.
(b) Rho, H. S.; Oh, S. H.; Lee, J. W.; Lee, J. Y.; Chin, J.; Song, C. E.
Chem. Commun. 2008, 1208–1210.
Org. Lett., Vol. 14, No. 1, 2012
187

A study of concentration and temperature effects also
provides evidence that the dimer is an active catalytic
species. Due to silanediol self-recognition, the dimer is
the predominant species in solid state and in solution
g0.4 M.5a A significant increase in reaction yield occurs at
concentrations where catalyst self-association is observed,
while negligible activation occurs at catalyst concentrations
<0.2 M (Table 2). Decreasing the reaction temperature to
0 °C, where self-association is also favored, produced similar
yields at 48 h compared to room temperature.
Table 3. Anisidine Additiona
time
yield in
solvent-free
yield (%)
entry
catalyst
none
(h)
DCM (%)b,c
1
2
3
4
5
6
7
8
9
24
24
24
24
48
24
24
48
24
5
3
Table 2. Temperature and Concentration Effectsa
Ph3SiOH
9
4
Ph2Si(OH)2
4
ꢀ
1
20
21
24
40d
74
88
21
ꢀ
1
2
29
99c
ꢀ
4
4
silica gele
84
a All reactions performed with 1.5 equiv of indole at room temperature.
b Reaction is 2.0 M in DCM. c Yields reported as an average of 2 or more
replicates. See the Supporting Information for a table with standard
deviations and experimental procedures. d Performing this reaction in
toluene for 24 h affords a similar yield (35%). e 20 wt % catalyst loading.
concn of
catalyst
time
(h)
yield
(%)b
entry
reaction (M)
concn (M)
temp
1
2
3
4
5
6
7
8
2.0
1.0
0.50
0.05
2.0
2.0
2.0
2.0
0.4
0.2
0.1
0.01
0.4
0.4
0.4
0.4
rt
24
48
48
48
24
24
48
48
91
42
29
23
99
48
80
19
rt
rt
rt
(Figure 2). At concentrations below the level of self-
association (e.g. e0.01 M), no significant binding is
observed. Binding is only detectable (SiOH Δδ = 0.48 ppm)
upon increasing the concentration of silanediol to a level
where significant catalyst self-association is observed
(e.g., >0.2 M). This is in direct contrast to stronger silanediol
binding effects observed for neutral Lewis bases (e.g., DMF)
and anions (e.g., acetate and halide) where SiOH shifts
range from Δδ = 1.6 to 3.9 ppm.3,5 NMR shifts also
indicate that silanediols exhibit strong self-associative
H-bonding to form a dimer. This evidence is consistent with
the hypothesis that a dimeric complex (e.g., 6) exhibits stronger
H-bonding to activate the nitrostyrene. Crystallization of
silanediol 1 with diethyl ether demonstrates the favorable
formation of the dimeric complex in the presence of a Lewis
base.16 This cooperative mode of H-bonding is an important
distinction from the mode of activation proposed for a
thiourea and has important implications for catalyst design.17
Computational studies were performed to model the
cyclic dimer and to evaluate the enhanced acidity of com-
plex 13. Performing studies with B3LYP/6-31þG(d)
40
4
4
ꢀ20
a All reactions performed with 1.5 equiv of indole. b Without catalyst,
the yield is 4% at 4 °C (24 h) and 21% at 40 °C (48 h).
Similar patterns of reactivity were observed for the
Michael reaction with a more challenging Michael donor,
N,N-dimethyl-m-anisidine (Table 3).7c Simple silanols and
silanediols provide low catalytic activity at both 24 and 48 h,
and only silanediol 4 is active enough to catalyze the
reaction in good yield at 48 h. It is notable in this case
that the solvent-free conditions with silanediol 4 provide a
significant increase in catalytic activity, affording a 99%
yield for the addition product 11 in less than 24 h.
NMR binding studies were performed to investigate the
H-bonding of nitrostryene withsilanediol 4 compared with
other Lewis bases.15 We have previously reported strong
molecular recognition between silanediols and carbonyl
compounds; however, NMR studies show that silanediols
bind weakly to nitrostyrene based on the SiOH shift
(14) (a) Hair, M. L.; Hertl, W. J. Phys. Chem. 1969, 73, 4269–4276.
(b) Hair, M. L.; Hertl, W. J. Phys. Chem. 1970, 74, 91–94.
(15) For 0.01 M in C6D6, we have calculated the binding constant
between silanediol 4 and DMF to be 90.8 ( 0.4 Mꢀ1 while that with
trans-β-nitrostyrene is e6.5 ( 5.2 Mꢀ1. See ref 5 and Supporting
Information.
(16) Attempts to crystallize nitrostyrene with silanediols were un-
successful. Searching the Cambridge Structural Database (October 26,
2011) provides no X-ray evidence supporting binding to nitrostyrene in a
dual hydrogen-bonding fashion.
(17) Kinetic studies are currently underway. For examples where
kinetic studies of catalytic systems have been used to elucidate reaction
mechanisms and improve catalyst design, see: (a) Vachal, P.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 10012–10014. (b) Leighton, J. L.;
Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924–10925.
(11) The addition of indole was selected for an accurate comparison
of catalytic ability due to the low background rate. Using methoxyindole
proceeds with a background rate of 35ꢀ40% yield in CH2Cl2.
(12) Silanediols 1ꢀ4 were prepared from the corresponding diarylsi-
lanes. See Supporting Information for details.
(13) Acidity calculations were conducted with B3LYP/6-31þG(d)
using Gaussion03. The geometries were fully optimized, frequencies
were calculated, and pKa values were verified by comparison to experi-
mental data for known acids, including orthosilicic acid, dimethylsila-
nediol, and triethylsilanol. See Supporting Information for complete
details.
188
Org. Lett., Vol. 14, No. 1, 2012

Scheme 2. Computational Study of Dimer Formation and
Acidity for pKa in H2O Using B3LYP/6-31þG(d)
In conclusion, we have demonstrated the importance of
cooperative H-bonding effects and SiOH-acidification for
silanediol catalysis. The self-recognition of the silanediol
creates a unique dimeric structure with enhanced H-bond-
ing capabilities that is not observed with most organoca-
talysts. We propose that this cyclic dimer is the pre-
dominant catalytic species capable of activating carbonyls
and Lewis bases (e.g., nitro groups) as electrophiles.
Evidence for this mode of H-bonding activation is based
on concentration effects observed, NMR binding, struc-
tural studies, computational studies, and enhanced activity
observed for solid-state reactions (i.e., solvent-free conditions).
Based on the cooperative H-bonding, silanediols provide a
new mode of activation for catalyst design as well as a
model to study SiOH acidification and surface reactivity of
silica gel for organic transformations. These studies also
provide important insight for catalyst design, particularly for
consideration of asymmetric catalysis, which must take into
consideration the self-recognition properties of silanediols.
Figure 2. NMR binding studies (400 MHz, in C6D6) with silanediol
4 and X-ray crystal structure of silanediol 1 binding to a Lewis base
...
˚
(e.g., diethylether). H-bond distances for SiꢀOH OꢀSi = 1.95 A
...
˚
(average) and SiꢀOH OEt2 = 1.80ꢀ1.96 A.
demonstrates that the formation of the cyclic dimer en-
hances the acidity of the SiOH by 1ꢀ2 pKa units through a
type of “OH-acidification” (Scheme 2).13,18 Thus, at con-
centrations of significant catalyst self-recognition, the cyclic
dimer is the dominant catalytic species due to its greater
acidity and consequently stronger activation. Overall, the
catalytic ability of silanediols is attributed to a balance
between the SiOH acidity, the solubility of the silanediol,
and access to the cyclic dimer with enhanced H-bonding
capabilities.
Acknowledgment. We acknowledge the University of
California, Davis, and National Science Foundation (CHE-
0847358 and Teragrid resources provided by the Pittsburgh
Supercomputer Center) for support of this research. A.K.F. is
a recipient of a 3M Nontenured faculty grant, and N.T.T.
acknowledges the United States Department of Education for
a GAANN fellowship. S.O.W. and N.T.T. are recipients of
the UC Davis Borge Fellowship.
(18) The effect of OH-acidification by H-bonding catalysis has been
previously reported for TADDOL molecules. When cooperative intra-
molecular H-bonding is prevented, then the acidity is dramatically
reduced; see: (a) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5846–5850. (b) Christ, P.; Lindsay,
A. G.; Vormittag, S. S.; Neudorfl, J.-M.; Berkessel, A.; O’Donoghue,
A. C. Chem.;Eur. J. 2011, 17, 8524–8528.
Supporting Information Available. Experimental pro-
cedures, spectral data for all compounds, NMR binding
studies, crystallography, and computational data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
€
Org. Lett., Vol. 14, No. 1, 2012
189