Sugar complexation to silicone boronic acids

Article abstract of DOI:10.1039/c2cc37438b

A new class of surface-active compounds based on the combination of silicones and boronic acids is described. The properties of the compounds can be tuned by manipulation of both the hydrophobic (silicone size and 3D structure) and hydrophilic components (by binding different saccharides to the boronic acid). Stabilization of the four-coordinate boron structure is provided by Tris buffer that also maintains neutral pH to suppress silicone hydrolysis.

Full text of DOI:10.1039/c2cc37438b

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Sugar complexation to silicone boronic acids†
Michael A. Brook,* Laura Dodge, Yang Chen, Ferdinand Gonzaga and
Hazem Amarne
Cite this: DOI: 10.1039/c2cc37438b
Received 11th October 2012,
Accepted 20th December 2012
DOI: 10.1039/c2cc37438b
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A new class of surface-active compounds based on the combi-
The stability of boronate complexes is affected by the pH of
nation of silicones and boronic acids is described. The properties of the solution and the presence of any Lewis base. For example,
the compounds can be tuned by manipulation of both the hydro- the equilibrium between tri- 1 and tetracoordinate 2 boron
phobic (silicone size and 3D structure) and hydrophilic components compound favours the latter when Lewis bases are present,
(by binding different saccharides to the boronic acid). Stabilization including hydroxide at higher pH.9 The equilibrium is also
of the four-coordinate boron structure is provided by Tris buffer affected by the R group on the boronic acid: arylboronic acids
that also maintains neutral pH to suppress silicone hydrolysis.
are more acidic than alkylboronic acids; and bulky substituents
surrounding boron can cause a decrease in acidity due to
Silicones are both highly mobile (Tg o 123 1C)1 and hydrophobic restricted access of water to the p-orbital on boron.10
entities (surface energy 23 mN mꢀ1)2 and, as a consequence, are
Many applications of boronic acids rely on binding selectivity for
widely used – depending on formulation – as both foaming and specific 1,2- or 1,3-diol sites 3, which are particularly prevalent on
defoaming agents.3,4 When combined with hydrophilic entities,5 saccharides (Fig. 1). This specificity has led to the use of boronic
particularly poly(ethylene glycol) and other polyether oligomers, they acids as tunable sensors for saccharides: the structure of a given BA
exhibit surface activities that cannot be matched by either fluoro- will determine to which sugar it will preferentially bind. Based on
carbon- or hydrocarbon-based surfactants. Silicone surfactants are selective binding several in vivo applications for BAs, such as drug
used in applications ranging from polyurethane foam stabilization3 delivery devices11 and artificial lectin (sugar binding protein)
to delivery of agricultural bioactives.6
mimics,12 have been proposed. Key to the utility of boronic acids
It would be of interest to develop responsive surfactants, whose in such applications is the very large range of binding constants –
properties could be manipulated by external stimuli including pH, over three orders of magnitude – for sugars with different diol
temperature, etc. Silicones are exceptionally stable near neutrality, stereostructures.13,14 Stability of the cyclic products is enhanced
but are subject to hydrolytic cleavage and depolymerization away when good Lewis bases are present 4.
from pH 7.7 Amino- or carboxylic acid-modified silicones are readily
Silicone-modified boronic acids should be interesting, tuneable
available, but are not normally used as surfactants due to the surfactants. If the presence of the hydrophobic silicone does not
associated pH sensitivity. As part of an examination of other significantly affect the sugar binding properties of the boronic acid,
potentially responsive organic functional groups, we chose to it should be possible to modify the surface activity by controlling the
establish if boronic acids could be incorporated on a silicone size (length of linear polydimethylsiloxane chains) and 3D structure
backbone and used to mediate surface activity of the silicone.
(the presence of branching in the silicone moiety) of the silicone
Boronic acids (RB(OH)2, BA) provide a highly flexible functiona- hydrophobe, and also the hydrophilicity of the boron head group by
lity that can be manipulated using a number of well-studied manipulating the type and size of hydrophilic sugar to which the
procedures. Not only can they be used in carbon–carbon bond boron is temporarily grafted. We report the first synthesis of silicone
forming reactions such as the Suzuki–Miyaura cross-coupling,8
but the boronic acid hydroxyl groups provide pH-sensitive binding
sites for appropriate diol-containing substrates.
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main
St. W., Hamilton ON, Canada L8S 4M1. E-mail: mabrook@mcmaster.ca
† Electronic supplementary information (ESI) available: NMR of 7 before and after
hydrolysis to 13 in the absence and presence of Tris; full experimental protocols and
characterization for compounds 7–12 (Table 1); hydrolysis and sugar binding protocols;
Fig. 1 Boronate-diol binding equilibria.15
and complex viscosity from rheolgoical data for 17 and 18. DOI: 10.1039/c2cc37438b
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Table 1 Preparation of silicone boronate esters
boronic acids (SBAs) and provide preliminary data demonstrating
their ability to differentially bind saccharides.
4-Vinylphenylboronic acid (styrylboronic acid) 5 is a convenient
starting material to which silicones can be grafted using the efficient
hydrosilylation process.16 Initial attempts to directly perform hydro-
silylation on vinyl-substituted boronic acids, including 5, were
unfortunately only sporadically successful. Active hydrogen com- H-functional
siloxane
Yield
(%)
Ratio T : I
(term : int)
pounds including carboxylic acids and alcohols are known to react
with Si–H groups to form H2 and siloxanes in a process that can
RR0R00SiH
Producta
Monofunctional linear
7
compete with the desired addition to alkenes, which is likely the
origin of the inconsistent results.17 It was necessary, therefore, to
protect the B–OH groups. Although several protecting groups were
examined many, including catecholates,18 proved to be too stable to
subsequent reactions: the conditions necessary for catecholate hydro-
lysis, for example, led to silicone redistribution/depolymerization.7
Therefore, a high yielding two-step synthesis was developed that
required little purification and for which by-products were not
observed (Fig. 2). Dimethyl-L-tartrate boronic ester 6 was formed
from the reaction of 5 with dimethyl tartrate. Simple dehydration
using molecular sieves afforded 6 in near-quantitative yield, and
required no purification prior to use in the subsequent reaction. The
second step utilized platinum-catalyzed hydrosilylation of the
protected acid 6 using Karstedt’s catalyst at room temperature
(Table 1). Compounds 7, 8, and 10–12 demonstrate the ability to
vary the size of polydimethylsiloxane hydrophobes, while compound
9 has a different connectivity (branched 3D structure) between the
hydrophobe and boronic acid moieties. The silicone-boronate
compounds were isolated in good to excellent yield as a mixture
of regioisomers that were inseparable by silica chromatography:
their relative concentrations could be determined by 1H NMR. Such
regioisomeric mixtures during hydrosilylation are particularly
problematic with aryl-substituted olefins.16
87
59
10 : 7
10 : 7
8
Branched
61
5 : 2
9
Difunctional (a,o)
10
54
2 : 1
81
76
5 : 4
5 : 4
11
12
Prior to examining the ability of the silicone boronic acids to
complex with sugars, the protecting tartrate had to be removed.
a
Shown for terminal regioisomer. The boronic acid products after
hydrolysis (Fig. 2) are compounds 13, 14, 15, 16, 17 and 18.
Actually, it was necessary to maintain an anhydrous environ-
ment during the hydrosilylation to form compounds 7–12
because the tartrate boronic ester was very susceptible to
hydrolysis (Fig. 2). Silicone-boronic acids were liberated from
their tartrate protecting groups to give 13t,i–18t,i simply by
treatment with PBS buffer within the pH range of 4.5 to 9.0.
This was readily determined by observing changes in the
chemical shift of diagnostic signals within the 1H NMR spectra
(for compound 7, see ESI†).
The resulting free boronic acids were relatively insoluble in
water, which is not surprising given the hydrophobicity associated
with silicones: even with the small disiloxane, the hydrophobic
group trumped the hydrophilic boronic acid. However, this beha-
viour could be altered by altering the character of the boronic acid.
The preference for boronic acid binding to fructose over
glucose was first observed by Lorand and Edwards19 and has
since become accepted as a common property of many boronic
acids.13 The ability of free boronic acid 13i,t to bind fructose or
glucose, respectively, in D2O was examined using 1H NMR
spectroscopy. The chemical shifts of relatively isolated aromatic
Fig. 2 Tartrate protection of 4-vinylphenylboronic acid and synthesis of silicone-
boronic esters 7–12 (for RR0R00, see Table 1).
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low. Upon hydrolysis, dramatic changes occurred leading to
increases in viscosity of several orders of magnitude (for
complex viscosities of 17 and 18, see ESI†). Normally, the
viscosities of homologous polymers track with chain length.
In this case, however, the density of boronic acid groups is
more important, as shown by the higher viscosity exhibited by
the silicone with shorter chain lengths. We propose that
segregation of boronic acids from silicones act as physical
crosslinks leading to the significant change in viscosity.
Boronic acids offer a series of interesting properties based on
their ability to reversibly and selectively bind diols, particularly
those affiliated with saccharides. New silicone surfactants based
on boronic acids have been prepared using a straightforward
synthetic strategy. The hydrophilic boronic acid termini allow for
these surface-active materials to bind selectively to cis-diols
of biologically interesting molecules, changing their surface
activity. The self-affinity of boronic acids in a silicone environ-
ment suggests their broader use to structure silicone networks.
We gratefully acknowledge the financial support of the
Natural Sciences and Engineering Research Council of Canada
and 20/20: NSERC Ophthalmic Materials Network for financial
support.
Fig. 3 Selective sugar binding of 7 with fructose in PBS pH 7.4/DMSO-d6.
proton peaks were monitored for changes due to binding at
boronic acid. In particular, the signals near 7.6 and 7.1 ppm
(Fig. 3) were diagnostic for changes in the environment near
boron. There was no change in the spectrum for silicone-boronic
acid exposed to glucose in solution, however, upon exposure to
fructose a new set of peaks was observed. Integration of these
peaks with respect to the unbound compound signals demon-
strated that approximately one-third of the silicone-boronic acid
in solution was bound to fructose: as would be expected for
boronic acids, no binding to glucose was observed. The fructose
complex of 13i,t exhibited enhanced water solubility: the solubility
nearly doubled compared to the free boronic acid (ESI†); however,
it was not possible to measure a critical micelle concentration for
any of the compounds. Larger silicones such as 11 could be
compatibilized with water by complexation with fructose. Thus, as
with other boronic acids, the binding of SBAs to saccharides was
dependent on diol structural characteristics.13,20
Notes and references
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dependent on the pH of solution and the presence of Lewis bases.
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silicone hydrolysis, particularly of the branched trisiloxane com-
pound 15.2 Fortunately, Lewis bases that favour formation and
also stabilize against hydrolysis the tetracoordinate complex 4
(Fig. 1) are readily available. An examination of a series of buffers
showed that tris(hydroxymethyl)amine (Tris) was particularly
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