NMR and X-ray studies of hydrogen bonding for amide-containing silanediols

Article abstract of DOI:10.1021/om300736n

The synthesis, isolation, and hydrogen-bonding properties of a series of amide-containing silanediols are described, including an enantioenriched silanediol. By incorporation of a 2,4,6-trimethylphenyl (mesityl) group, these functionalized silanediols are isolable by column chromatography and stable in the presence of standard acids (e.g., AcOH) and bases (e.g., NH₄OH). NMR spectroscopy and X-ray crystallography provide evidence for the conformational rigidity and binding properties of amido-silanediols based on the parameters (e.g., sterics, hybridization, and ring size of hydrogen bonding) that affect intra- and intermolecular hydrogen bonding. Pyridine binding studies demonstrate that these conformational effects have implications for the existence of single versus multiple modes of hydrogen bonding.

Full text of DOI:10.1021/om300736n

Communication
pubs.acs.org/Organometallics
NMR and X‑ray Studies of Hydrogen Bonding for Amide-Containing
Silanediols
Sean O. Wilson, Ngon T. Tran, and Annaliese K. Franz*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: The synthesis, isolation, and hydrogen-bonding
properties of a series of amide-containing silanediols are
described, including an enantioenriched silanediol. By
incorporation of a 2,4,6-trimethylphenyl (mesityl) group,
these functionalized silanediols are isolable by column
chromatography and stable in the presence of standard acids
(e.g., AcOH) and bases (e.g., NH4OH). NMR spectroscopy
and X-ray crystallography provide evidence for the conforma-
tional rigidity and binding properties of amido-silanediols
based on the parameters (e.g., sterics, hybridization, and ring
size of hydrogen bonding) that affect intra- and intermolecular
hydrogen bonding. Pyridine binding studies demonstrate that
these conformational effects have implications for the existence of single versus multiple modes of hydrogen bonding.
norganic and organic silanols exhibit unique hydrogen-
bonding capabilities that are important for materials, surface
expected to play an essential role in their three-dimensional
structure and biological function.8 Research in this area often
focuses on the development of synthetic methodology to access
silanediol precursors;3 therefore, very few studies have been
reported that describe the intramolecular hydrogen bonding
and conformational preferences for functionalized silanediols.9
Computational studies of amide-containing silanediols demon-
strate the effect of intramolecular hydrogen bonding on rigidity
and conformation: if the correct conformation is obtained, a
more rigid structure is expected to have better binding to a
receptor due to a lower entropic penalty.10 There is a need to
access soluble silanediols that are stable toward condensation
and desilylation in order to improve our understanding of the
parameters affecting the conformational and hydrogen-bonding
abilities of this class of compound.
I
chemistry, catalysis, and medicinal chemistry.1 Organosilanols
in several different forms have been investigated as isosteres in
drug design and demonstrated to exhibit biological activity
(Figure 1). For example, Tacke has reported silicon analogues
Here we demonstrate the synthesis of a new series of stable
and isolable amide-containing silanediols 1−4 for the purpose
of understanding their intramolecular hydrogen bonding
(Figure 2). This series of structurally related silanediols has
been selected to compare different electronic effects, steric
effects, the chiral center, the position of the silanediol, and ring
size for intramolecular hydrogen bonding. The synthesis of new
functionalized silanediols can be challenging because difficulties
can be encountered due to self-condensation and oligomeriza-
tion of the silanediol. Therefore, the ability to access more
acidic aryl silanediols relies on the incorporation of bulky
substituents surrounding the silicon atom in order to minimize
self-condensation.11 Previously, we have utilized a 2,4,6-
trimethylphenyl (mesityl) group as a general strategy for steric
Figure 1. Biologically active silanols and silanediols.
of the dopamine (D2) receptor antagonists,2 and Sieburth has
pioneered the synthesis and study of silanediol peptide
analogues as protease inhibitors.3 Silanetriols, which can be
stabilized by the use of bulky substituents, have recently been
found to provide reversible inhibition of acetylcholinesterase
(AChE) activity.4 Antimicrobial activities of trialkylsilanols have
also been reported where silanols exhibit greater biocidal
properties relative to carbon analogues, which is attributed to
the enhanced hydrogen-bond acidity as well as the lip-
ophilicity.5 Our laboratory6 and others7 have also studied the
hydrogen-bonding properties of silanols and silanediols for
applications in molecular recognition and catalysis.
As with biomolecules such as peptides and carbohydrates, the
intramolecular hydrogen bonding of bioactive silanediols is
Received: August 1, 2012
Published: September 18, 2012
© 2012 American Chemical Society
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Scheme 2. Synthesis of Enantioenriched Silanediol 4
Figure 2. Silanediols synthesized and investigated here.
shielding in order to overcome self-condensation and improve
the solubility of aryl silanediols.6a−c
Aryl amides 5a−c, with different steric and electronic effects,
were investigated to access silanediols 1−3 (Scheme 1). A
catalysts. Silanediols 3 and 4 (10 μM) exhibit no degradation
when stored at room temperature in CDCl3 solvent or a
mixture of CD3CN/D2O after 7 days (see the Supporting
Information). The stability in the presence of acid or base was
also investigated. When silanediols 3 and 4 were monitored in
the presence of AcOH (0.9 M) or excess NH4OH (1.3 M), the
1H NMR spectra also remained unchanged after 7 days. Upon
addition of trifluoroacetic acid (0.1 M), rapid degradation (e.g.,
condensation and/or desilylation) of both silanediols is
observed, on the basis of the disappearance of the characteristic
peaks in the NMR spectra. The production of mesitylene along
with broad, multiple new peaks suggests a combination of
protodesilylation and condensation to form oligomeric
siloxanes.
Scheme 1. Synthetic Route to Silanediols through
Lithiation−Silylation Methodolgy
NMR spectroscopy demonstrates that structurally related
silanediols 1−4 exhibit intramolecular hydrogen bonding with
1
lithiation−silylation strategy with mesitylchlorosilane in the
presence of TMEDA affords silanes 6a−c in moderate yields
following standard column chromatography procedures. Phenyl
silicon electrophiles were not used because previous inves-
tigations resulted in lower yields of silanes and the products
were more prone to decomposition without the shielding effect
of the 2,4,6-trimethylphenyl (mesityl) group.
different conformational rigidities (Figure 3). H NMR spectra
Metal-mediated hydrolysis of the Si−H bond affords
silanediols 1−3 in good yields using catalytic Pd/C with H2O
in THF.12 This hydrolysis method utilizes mild conditions that
do not promote condensation of the silanediol product.6a−c,13
Silanediols 1−3 can be purified using standard column
chromatography conditions with no decomposition observed.14
1
The silanediol structures have been confirmed using H, 13C,
and 29Si NMR spectroscopy, and HRMS.
Chiral, nonracemic silanediol 4 was accessed using an
enantioselective lithiation−silylation strategy with benzylamide
7 (Scheme 2).15 The (−)-sparteine-mediated asymmetric
addition of mesitylchlorosilane to the benzylic position affords
silane 8 with moderate enantioselectivity (76:24 er).16,17 Silane
8 can be hydrolyzed to the enantioenriched, chiral silanediol 4
using Pd/C in the presence of 5 equiv of H2O. The absolute
stereochemistry was assigned by analogy to similar structures
reported in the literature.16 The racemic silanediol 4 is readily
obtained by replacing (−)-sparteine with TMEDA.
Figure 3. Hydroxyl peaks of silanediols 1−4 (10 mM in C6D6) as
visible by 1H NMR spectroscopy. Silanediols 3 and 4 contain
chemically inequivalent hydroxyl peaks at room temperature,
suggesting rigid intramolecular hydrogen bonding under ambient
conditions.
of silanediols 4 and 3 each exhibit two distinct hydroxyl signals
with a large chemical shift difference (2.16 and 1.97 ppm,
respectively, Figure 3A,B), which is attributed to a single
conformation of intramolecular hydrogen bonding. For
silanediols 1 and 2, the same intramolecular hydrogen bonding
is proposed between the amide and one of the hydroxyl groups;
however, only a single broadened peak is observed, suggesting
that a rapid equilibrium exists between conformers (Figure
3C,D). In the case of silanediol 4, the single conformation is
1
We have utilized H NMR spectroscopy to monitor the
stability of silanediols 3 and 4 (i.e., toward condensation to
afford siloxanes or desilylation).2a,3a,18 Isolation of discrete
silanediols is necessary for the accurate and reproducible study
of hydrogen-bonding interactions. Understanding the stability
of silanediols under various conditions provides insight into
their potential utility as medicinal compounds and organo-
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attributed to the ring size of intramolecular hydrogen bonding
and hybridization of the carbon attached to silicon. In the case
of silanediol 3, the enhanced rigidity and preference for a single
conformation is attributed to the increased steric effect of the
case of silanediol 2, the silanol peak progressively broadens
upon increasing the amount of pyridine (see Figure S2 in the
Supporting Information), suggesting multiple modes of intra-
and intermolecular binding. The difference in binding behavior
between these comparable silanediols demonstrates how
intramolecular hydrogen-bonding ring size, hybridization, and
steric effects each play a role to affect intermolecular
interactions and therefore all have important implications for
the design of silanol-based medicinal compounds and hydro-
gen-bonding catalysts.
The X-ray structure of amide silanediol 3 confirms
intramolecular hydrogen bonding between the amide and
silanol group, with additional intermolecular hydrogen-bonding
interactions affording a dimeric complex with a bridging water
molecule (Figure 5). An additional hydrogen bond is also
naphthyl group relative to the phenyl derivatives.19 When H
1
NMR spectroscopy is performed at low temperature for
silanediol 2 in CDCl3, the geminal silanol peaks are resolved
at −40 °C and a single conformation can be observed (see
Figure S1 in the Supporting Information). Additional analysis
of silanediols 1−4 using IR spectroscopy suggests that several
modes of hydrogen bonding exist (in the solid state), on the
basis of the observation of a single broad O−H peak.20
Understanding the parameters affecting the intra- and
intermolecular hydrogen-bonding properties of silanediols is
important for specificity in both biological applications and
organocatalysis. Using pyridine binding studies, we have
monitored the adoption of various binding motifs based on
chemical shifts of silanediols 2−4 using 1H NMR spectroscopy
in the presence of varying equivalents of pyridine (see Figure
S1 in the Supporting Information).21 For each silanediol,
significant chemical shifts (up to 1.23 ppm) are observed for
the silanol signal, demonstrating the presence of intermolecular
hydrogen-bonding interactions with pyridine; however, distinc-
tive peak shape and broadening patterns are observed for each
silanediol. Peak shape in NMR spectroscopy is often used as
evidence of single-mode binding between small molecules and
proteins.22 In the case of silanediols 3 and 4, for which two
distinct silanol peaks are observed, the upfield silanol proton
has a significantly greater change in chemical shift (Δδ = 1.23
ppm for 3 and 0.88 ppm for 4) in comparison to the downfield
silanol proton (Δδ = 0.37 ppm for 3 and 0.40 ppm for 4). With
silanediol 4 a significant initial broadening of both silanol peaks
is observed up to the addition of 4 equiv of pyridine. Upon
addition of an excess of pyridine (5 equiv), both silanol peaks
sharpen, suggesting the transition to a single mode of pyridine
binding (Figure 4). Although a similar change in chemical shift
was also observed for silanediol 3, the peak shape remains
constant at various amounts of pyridine (see Figure S3 in the
Supporting Information), which is attributed to a more rigid
system that generally favors a single mode of binding. In the
Figure 5. X-ray crystallographic analysis of silanediol 3, affording a
dimeric complex that confirms amide intramolecular hydrogen
bonding and incorporates a bridging H2O molecule.
observed between the amide and water molecule. The bridging
water molecule is incorporated into the dimeric species through
absorption of atmospheric water. We have previously observed
that bulky diaryl silanediols self-associate through intermolec-
ular hydrogen bonding to form a cyclic dimer, which exhibits
strong hydrogen bonding with neutral Lewis bases (e.g., DMF,
Et2O, PhCHO) on the basis of X-ray and NMR binding
studies.6a−c,23 Here, the amide functionality and bridging water
molecule contribute to a unique network of hydrogen bonding
observed in the X-ray structure for silanediol 3. This
combination of intramolecular and cooperative hydrogen
bonding provides valuable insight for the design of medicinal
compounds and also has implications for understanding the
interactions of water and organic molecules with heterogeneous
silica.24
In conclusion, we have demonstrated the effect of intra-
molecular hydrogen bonding on molecular conformation and
intermolecular binding modes for a series of structurally related
silanediols. Through incorporation of a bulky mesityl
substituent, amide silanediols are soluble in organic solvents,
are readily isolated through column chromatography, and are
stable under standard acidic or basic conditions. Using NMR
spectroscopy, a comparison of silanediols 1−4 demonstrates
that steric effects, silanol attachment (e.g., sp2 vs sp3), ring size
of intramolecular hydrogen bonding, and temperature all play
an important role in dictating the conformational rigidity of
amide-containing silanediols. These conformational effects have
1
Figure 4. H NMR spectroscopy binding studies of silanediol 4 (10
mM in C6D6) with increasing equivalents of pyridine.
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intermolecular hydrogen bonding, as demonstrated through
binding studies with pyridine. X-ray crystallography demon-
strates the ability of amide silanediols to form a unique
hydrogen-bonding network with intramolecular hydrogen
bonding and incorporation of a bridging water molecule. It is
expected that the results of this study can be used to design and
study the hydrogen-bonding preferences of new peptidomi-
metic silanediols and organocatalysts.
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ASSOCIATED CONTENT
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S
* Supporting Information
Text, tables, figures, and a CIF files giving experimental
procedures, spectral data for all compounds, NMR and IR
spectra, pyridine binding studies for silanediols 2 and 3, and
crystallographic data for 3 (CCDC 884477). This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: akfranz@ucdavis.edu.
Notes
(14) Although the silane was isolated here for characterization
purposes, further experiments demonstrated that the unpurified silanes
6a−c can be directly hydrolyzed to afford silanediols with similar
overall yields.
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The authors declare no competing financial interest.
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■
We acknowledge the National Science Foundation (CHE-
0847358) for support of this research. A.K.F. is a recipient of a
3M Nontenured faculty grant. S.O.W. and N.T.T are recipients
of the UC Davis Borge Fellowship. N.T.T. is a recipient of an
Achievement Rewards for College Scientists (ARCS) Scholar-
ship and also acknowledges the United States Department of
Education for a GAANN fellowship.
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