Organosilane Chemical Gradients: Progress, Properties, and Promise

Invited Feature Article pubs.acs.org/Langmuir

Organosilane Chemical Gradients: Progress, Properties, and Promise Maryanne M. Collinson*,† and Daniel A. Higgins*,‡ †

Department of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Richmond, Virginia 23284-2006, United States ‡ Department of Chemistry, Kansas State University, 1212 Mid-Campus Drive North, Manhattan, Kansas 66506-0401, United States ABSTRACT: Chemical gradients play an important role in nature, driving many different phenomena critical to life, including the transport of chemical species across membranes and the transport, attachment, and assembly of cells. Taking a cue from these natural processes, scientists and engineers are now working to develop synthetic chemical gradients for use in a broad range of applications, such as in high-throughput investigations of surface properties, as means to guide the motions and/ or assembly of liquid droplets, vesicles, nanoparticles, and cells and as new media for stationary-phase-gradient chemical separations. Our groups have been working to develop new methods for preparing chemical gradients from organoalkoxysilane and organochlorosilane precursors and to obtain a better understanding of their properties on macroscopic to microscopic length scales. This review highlights our recent work on the development of controlled-rate infusion and infusion-withdrawal dip-coating methods for the preparation of gradients on planar glass and silicon substrates, on thin-layer chromatography plates, and in capillaries and monoliths for liquid chromatography. We also cover the new knowledge gained from the characterization of our gradients using sessile drop and Wilhelmy plate dynamic water contact angle measurements, Xray photoelectron spectroscopy mapping, and single-molecule tracking and spectroscopy. Our studies reveal important evidence of phase separation and cooperative interactions occurring along multicomponent gradients. Emerging concepts and new directions in the preparation and characterization of organosilane-based chemical gradients are also discussed.

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INTRODUCTION

The preparation, characterization, and applications of chemically graded materials have been described in detail in recent reviews.1−3 Gradients have been prepared from organic polymers that were either physically coated or chemically grafted onto substrates.41,42 They have also been prepared by the self-assembly of organothiol monolayers on noble metal surfaces (e.g., gold).43−45 When gradients are to be prepared on oxide surfaces, organoalkoxysilane and organochlorosilane precursors provide simple routes to robust materials. Gradients ranging from self-assembled monolayers to thin films and even monoliths can be obtained from the wide variety of commercially available organosilane precursors. However, despite their significant potential, much remains to be learned about the preparation of organosilane gradients and their physicochemical properties on macroscopic to microscopic levels. Our research groups have spent the last several years working to develop new self-assembly and sol−gel-based approaches for preparing chemically graded materials from organoalkoxysilane and organochlorosilane precursors. Figure 1 depicts the basics of these approaches and some examples of the materials that can be prepared. This article provides an overview of our work to date. After a brief presentation of background material, we

Synthetic surface and thin-film chemical gradients are now being developed for use in a wide variety of fundamental and technological investigations spanning fields from chemical biology to materials science. Chemical gradients comprise materials incorporating gradual spatial variations in composition and/or physical properties such as thickness, density, wettability, viscosity, charge, and porosity; they are also known as chemically graded materials.1−3 Compositional variations may involve changes in the concentration of one or more chemical constituents along one, two, or even three dimensions.1−3 Physical property variations may arise directly from the compositional variations, or they may be separately engineered during materials synthesis. The resulting gradients are usually manifested over macroscopic distances (i.e., centimeters) but may be designed to appear on much shorter length scales. Synthetic chemical gradients were first purposefully prepared in the late 1980s4 and are now being employed in high-throughput investigations of adsorption, desorption, and adhesion phenomena;4−12 as new materials for chemical sensing13,14 and catalysis;15 as a means to study surface wetting,16−20 solvent-induced surface rearrangement,21 and phase-separation phenomena;22,23 as stationary phases for chemical separations;24−31 and as a means to induce the spontaneous motions of liquid droplets,32−35 vesicles,36 nanoparticles,37 macromolecules,38 and cells.39,40 © XXXX American Chemical Society

Received: June 30, 2017 Revised: August 8, 2017

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DOI: 10.1021/acs.langmuir.7b02259 Langmuir XXXX, XXX, XXX−XXX

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Invited Feature Article

Figure 1. Silane gradients are frequently prepared on base-layer-coated substrates designed to present a high density of surface silanol sites. Base layers may be created by spin coating a silica sol onto the substrate (top). Gradients can be prepared on base-layer-coated substrates by a variety of methods, including vapor diffusion, controlled-rate infusion, and infusion-withdrawal dip coating using commercially available organosilane precursors (middle). Two-component gradients are obtained by depositing a silane on the base layer (bottom left), with the chosen silane and the silanol groups comprising the two components. Three-component gradients are obtained by depositing two silanes, with the silanol sites again acting as a third component (bottom right). When two or more components are employed, either aligned or opposed gradients can be formed. Aligned gradients are particularly interesting because the different functional groups are in close proximity to each other, facilitating cooperative interactions.

review the new methods we have developed to produce organosilane gradients of controlled profile (i.e., steepness) and composition. We then discuss methodologies for evaluating their macroscopic to microscopic properties. We have characterized the chemical and physical properties of our gradients using techniques such as water contact angle goniometry, spectroscopic ellipsometry, X-ray photoelectron spectroscopy, Raman and infrared mapping, atomic force microscopy, and single-molecule detection and tracking. We finish by highlighting challenges, emerging concepts, and future developments relevant to both the fabrication and application of organosilane-based synthetic chemical gradients.

These precursors can be mixed with TMOS or TEOS and used to form a hybrid organic−inorganic gel. Alkylsiloxane monolayers/multilayers can be assembled on oxide surfaces by starting with mono-, di-, or trichlorosilanes.59−62 The chlorosilanes react quickly with surface −OH groups63 and any water that is present.64 Alkoxysilanes can also be employed, although these often require an acid or base to catalyze the reaction. Indeed, a base is also sometimes used with the chlorosilanes, acting to remove the HCl that is generated.65 As described below, functionalized chlorosilanes are frequently used to prepare gradients by vapor-phase32 or solution4 diffusion methods. The sol−gel process and silane chemistry afford many advantages that facilitate the formation of gradients. Most notably, processing takes place under ambient temperatures and pressures and does not require expensive instrumentation. Furthermore, a wide variety of organosilanes are commercially available, the chemistry is relatively simple, and organosilanes can be easily grafted onto any surface that contains SiOH functionalities. For surfaces that lack these groups, sol−gel chemistry can be used to create a coating incorporating SiOH groups by spin-coating or dip-coating methods. The Si−O−Si bond is fairly strong, and the materials thus produced are thermally and chemically stable, at least for pH > 2 and pH < ∼9.

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BACKGROUND Sol−gel chemistry is a versatile approach to preparing inorganic and organic−inorganic hybrid materials. The sol−gel process has been studied in great detail, and a number of reviews and books have been published on the subject.46−48 In brief, it involves the hydrolysis and condensation of reactive metal alkoxides, leading to the formation of a sol and eventually a gel.47 For silica materials, which are the subject of this article, one often begins with Si(OR)4 where R = CH3 for tetramethoxysilane (TMOS) or R = CH2CH3 for tetraethoxysilane (TEOS). Typically, the silane is mixed with either methanol or ethanol and water. An acid or base is then added as a catalyst to increase the rate of hydrolysis and condensation. Thin films can be prepared by spin coating or dip coating the sol onto a suitable support.49,50 Monoliths can be prepared by allowing the sol to gel in a suitable container. The introduction of organic functionalities into the silica matrix can be achieved in a number of different ways.51−56 Molecules can be added to the silica sol, and these then become entrapped upon gelation.57,58 Alternatively, organoalkoxysilanes with the general formula (R′x−Si(OR)4−x) can be used. Here, R′ can be any of a variety of organic functional groups.53,56

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PROGRESS ON GRADIENT PREPARATION

Chemical gradients have been prepared by a wide variety of methods to date.1−3 Our focus here is primarily on the approaches used in our laboratories as well as closely related methods. These methods have the same attributes and limitations identified previously for the formation of nongradient self-assembled monolayers from organsilanes by closely related solution- and vapor-phase methods. These include the requirement that thin water films be present on the B


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substrate to facilitate attachment of the silanes64 and the expectation that surface roughness will alter the molecular order within the film.66 We have employed several of the methods described below to obtain gradients in wettability, polarity, acidity/basicity, charge, metal ion chelation, and biomolecule adsorption strength using functional groups such as alkanes, perfluoroalkanes, aryl rings, monoamines, diamines, triamines, thiols, sulfonic acids, and carbonitriles. The gradients obtained have been millimeters to centimeters in length, have exhibited property variations along one or two dimensions, and have been supported on or in a variety of silane base-layercoated planar and capillary-based substrates. Diffusion-Based Methods. One of the first approaches used to create silane-based chemical gradients involved the addition of organochlorosilane (e.g., dimethyldichlorosilane) in trichloroethylene to a container filled with xylene.4 Because trichloroethylene is more dense than xylene, it rested at the bottom of the container. A gradient was formed as the silane diffused into the xylene phase and bonded to a silicon or glass surface.4 Variations of this method were soon developed,67 with vapor diffusion becoming popular as a result of its simplicity.32 In this method, a volatile chlorosilane is dissolved in paraffin oil and the solution is placed a fixed distance from the substrate. The silane vapor diffuses over the substrate, where it reacts with surface hydroxyl groups. The edge of the substrate that is closest to the vapor source is most heavily modified, creating a gradient.32 Initial work involved the creation of wettability gradients that caused small drops of water to move uphill.32 Using this same approach, gradients were prepared from a number of different chloro- and alkoxide-based silanes, including 3-aminopropyltriethoxysilane (APTEOS),68−70 fluorinated mono- and trichlorosilane silanes,71,72 octyltrichlorosilane,73 and 3-cyanopropyltrichlorosilane.74 We have used the vapor diffusion approach to create gradients from octyltrichlorosilane that were used to elongate λ-DNA35 and from aminopropyltrimethoxysilane to study reversible potential-dependent binding of DNA at electrode surfaces.12 Multicomponent gradients and those with different profiles can also be created using variations of the vapor diffusion approach. For example, radial gradients have been prepared by placing the precursor reservoir directly above the substrate.75 Albert et al. showed that by manipulating the size and placement of the precursor reservoir, while restricting diffusion to a small gap under dynamic vacuum, linear multicomponent gradients with different steepnesses could be prepared.76 Using a similar approach, we have prepared multicomponent gradients from cyanopropyltrichlorosilane and n-octyltrichlorosilane.74 The net result was an opposed surface gradient rich in nitrile groups on one end and C8 hydrocarbon groups on the other. Alternatively, backfilling approaches can be used to produce a multicomponent gradient. For example, Souharce et al. first created a gradient by vapor diffusion with octadecyldimethylchlorosilane.77 The gradient that was initially formed was then exposed to perfluoroalkyldimethylchlorosilane vapor or to aminopropyltriethoxysilane in ethanol as a means to create a “dually-grafted” surface.77 Destructive Chemical Approaches. Another approach for preparing gradients involves the destruction of a selfassembled monolayer by exposure to ultraviolet radiation,33,78−80 an oxygen plasma,81 or a strong chemical oxidant.34 In work by Ito et al., wettability gradients were prepared by first soaking a substrate in dry toluene containing n-octadecyltri-

methoxysilane.33 Using a photomask and vacuum UV light, the alkylsilane was selectively photodegraded to yield the desired gradient. In another example, reported by Loos et al., gradient surfaces were produced by exposing a uniformly modified substrate to UV/O3 through a variable neutral density filter.79 Similar gradients have also been created by placing a substrate on a motorized stage and exposing the sample in a timedependent fashion to UV radiation.80 Contact Printing. Gradients can also be prepared by contact printing/stamping.82−84 In this approach, an ink (often an organochlorosilane in a suitable solvent) is applied to an elastomeric stamp and the stamp is then placed in contact with a hydroxylated substrate surface (e.g., an oxidized silicon wafer or glass). A gradient is created by varying the contact area and/ or contact time between the stamp and the surface. The longer the stamp is in contact with the surface, the greater the degree of modification. By varying the geometry of the stamp, gradients of different sizes and shapes can be prepared. Unlike diffusion-based methods, gradient steepness can be more easily controlled. Wettability gradients have been prepared using octadecyltrichlorosilane (OTS) in hexane as the “ink”.83 Nanoparticle gradients were also prepared by first forming a one-component gradient from OTS and then backfilling with 3aminopropyltrimethoxysilane, followed by exposure to a solution containing nanoparticles.82 A similar approach was used to fabricate a poly(ethylene glycol) (PEG) gradient to study protein adsorption and cellular binding, in this case, by backfilling with a PEG silane.84 Although stamping is timeefficient and allows for control over the gradient shape and profile, the silane ink must be efficiently transferred from the stamp to the substrate on a time scale that is similar to that of its surface reactions. Unfortunately, not all silanes are able to wet the elastomeric stamp.82 Controlled-Rate Infusion (CRI). CRI is a relatively simple time-based approach that we have developed to prepare silane gradients.85 This method involves the infusion of a solution containing reactive silane precursors into a container (e.g., a glass vial) housing a vertically aligned planar substrate or into the support (e.g., a capillary) itself. The general method is depicted in Figure 2A. The bottom of the substrate is exposed to the reactive solution for a longer time than the top, leading to the formation of a chemical gradient.85 The process can be repeated using the same substrate to prepare multicomponent gradients where the individual gradients either align with or oppose each other.86,87 Typical infusion times range from 2 to 30 min for substrates 2−10 cm in length. The gradients formed are often of near-monolayer thickness.87 For CRI to work, two conditions must be met: (a) the support must have a sufficient density of silanol groups on its surface and (b) the rate of the reaction between the silane precursors and surface silanols must match the rate of infusion. The former requirement can be met either by using supports with a high density of silanol groups such as a silica capillary,88 silica monolith,25 or a thin-layer chromatography plate24,26,86 or by coating the support with a TMOS-derived silica sol (i.e., a base layer) to form a uniform film with exposed silanol groups.89 The latter requirement has been met by using organoalkoxysilanes containing amine groups or by using a twostep hydrolysis−condensation approach.86 Because amine groups act as a catalyst for silanol condensation, aminefunctionalized silanes work well with CRI.26,90,91 We have prepared single and multicomponent gradients from a variety of different alkoxysilanes including mono-, di-, and triaminoalkC


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a different alkoxysilane (e.g., methyltrimethoxysilane, MTMOS) into the reservoir, while the other pump is used to withdraw the mixed sol. The sol meniscus is made to recede down the substrate surface either by setting the withdrawal rate higher than the infusion rate or by slowly pulling the substrate out of the reservoir. This method produces gradients 1−2 cm in length over the course of ∼45 min. The films obtained usually incorporate a thickness gradient because the reactivity of each precursor silane is different. In our initial demonstration, the film thickness ranged from ∼10 nm at the bottom (derived from MTMOS) to ∼130 nm at the top (from TMOS).93 Contact line pinning at the substrate surface during dip coating caused the meniscus to recede in a stick−slip fashion, leading to additional thickness variations on shorter length scales.

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GRADIENT PROPERTIES From the Macroscopic to the Microscopic. Synthetic gradients are often expected to exhibit continuous property variation. However, the multicomponent organosilane mixtures employed in our work are not always fully miscible, and phase separation94,95 can lead to gradients incorporating discrete domains that vary in size and composition. Careful characterization of gradient materials over a range of length scales is therefore required to verify that the desired gradient has been obtained and to ensure that its properties are fully understood. We have employed a battery of measurement tools for the characterization of gradient composition, wettability, polarity (i.e., dielectric constant), acidity or basicity, thickness, charge character, and morphology. These tools include X-ray photoelectron spectroscopy, Raman and infrared spectroscopy, water contact angle goniometry, single-molecule fluorescence detection using probe dyes, ellipsometry, zeta potential measurements, and atomic force microscopy. Methods that afford mapping and imaging capabilities have been particularly valuable because these have allowed for the gradients to be directly visualized85,90,96 and for domains formed along the gradients to be detected.89 Atomic and Molecular Composition (XPS, IR, and Raman). X-ray photoelectron spectroscopy (XPS) provides valuable elemental information on thin films and surfaces and has been widely employed by the Collinson group for the mapping of gradient composition.85,90 Many of the gradients we have prepared incorporate amine moieties; XPS mapping of film nitrogen content therefore provides clear evidence of gradient formation. Nitrogen content is determined from the areas under the N 1s peaks at ∼399 and ∼401 eV. The peak at 399 eV arises from free amines, and that at 401 eV is due to protonated or hydrogen-bonded amines.97 Figure 3 depicts representative results from one- and twodimensional (1D and 2D) gradients produced by CRI using an aminopropyltriethoxysilane-based sol. The 1D gradient was produced by exposing the substrate to aminosilane in a single infusion step. The 2D gradient was obtained by rotating the substrate 90° after the first deposition and subsequently exposing it to the aminosilane a second time. The amine content of the gradients was characterized by plotting the N 1s peak area as a function of position. These studies demonstrated that control over the gradient profile could be achieved in CRI by changing the rate of sol infusion into the deposition reservoir.85 XPS has also been used to map the amine content of gradients prepared from mono-, di-, and triaminosilane precursors using CRI.90

Figure 2. (A) Process used in controlled-rate infusion (CRI).85 (B) Apparatus used for infusion-withdrawal dip coating (IWDC). (C) Photograph of the reservoir used in IWDC. Panels B and C are reproduced from ref 93. Copyright 2010 American Chemical Society.

oxysilanes, mercaptopropylalkoxysilanes, cyanopropylalkoxy, and phenyltrimethoxysilane.24,26,85−88,90,91 CRI allows for gradient materials with different surface chemistries to be prepared. For example, the chemical composition of the base layer can be changed to modify the surface hydrophobicity/hydrophilicity.92 This can be used to strategically alter the surface wettability and the contact angle hysteresis, which determines whether spontaneous liquid droplet motion is possible.92 CRI also allows for the surface chemistry to be abruptly changed at specific locations along a gradient by simply changing the infusion rate.85,92 It can also be used to alter the position of individual functionalities relative to each other by aligning or opposing the individual gradients.87 Finally, with regard to technological applications, CRI is especially conducive to the formation of gradients inside columns and capillaries for liquid chromatography.25,86,88 Infusion-Withdrawal Dip Coating (IWDC). Another approach we have used to create relatively thick silane gradients on planar supports is termed IWDC.93 As in CRI, the substrate is coated with a TMOS-derived base layer prior to gradient formation. IWDC is similar to conventional dip coating except that in IWDC the substrate is immersed in a silica sol of timevarying composition. Figure 2B,C shows the apparatus employed. The substrate is first immersed in an initial sol (e.g., derived from TMOS). Two synchronized syringe pumps are then started. One of these infuses a second sol derived from D


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Figure 3. N 1s XPS data obtained from amine gradients prepared by CRI. (A) XPS spectra along a 1D amine gradient. Nitrogen is present as a free amine (∼399 eV) or as a protonated or hydrogen-bonded amine (∼401 eV). (B) Profile of the 1D amine gradient revealed by the N 1s peak area. (C) N 1s peak area for a 2D amine gradient prepared by CRI. Reproduced from ref 85. Copyright 2011 American Chemical Society.

Figure 4. Raman and water contact angle data obtained from a PTMOS−TMOS-derived gradient prepared by IWDC. (A) Raman spectra acquired along the gradient in the C−H stretching region. The spectra have been offset in the Y direction for better visualization. (B) Area under the phenyl C−H stretching peak at 3060 cm−1 along the gradient. (C) Sessile drop water contact angle data obtained along a similar gradient. Reproduced from ref 89. Copyright 2014 American Chemical Society.

Infrared absorption and Raman scattering spectroscopies can be used to characterize gradient composition at the functional group level. Figure 4A,B shows a representative example in which gradients prepared by IWDC from phenyltrimethoxysilane (PTMOS) and TMOS sols were characterized by detecting Raman scattering from the aromatic C−H stretch at 3060 cm−1.89 The Raman band at 2930 cm−1 was attributed to residual unhydrolyzed methoxy groups remaining in the film. PTMOS-derived gradients prepared on thin-layer chromatography (TLC) plates by CRI have also been mapped via diffuse UV reflectance spectroscopy,86 whereas other gradients incorporating methyl-modified silica were characterized by FTIR mapping.96 We have also mapped specific functional groups along gradients by classical colorimetric methods. For example, the amine content of gradients prepared on TLC plates by CRI has been characterized by exposing the plates to ninhydrin.24 Ninhydrin reacts with the surface-bound amine groups to form a purple dye that is readily detected in visible-light images of the gradients.98 Though simple, this method is not as sensitive as XPS. Acidity/Basicity and Charge Character (XPS and Zeta Potential). In addition to verifying the gradient profile, XPS mapping can also be used to characterize the acidity/basicity of gradient films. We have investigated the basicity of amine sites in the dry state along aminosilane gradients incorporating primary, secondary, and tertiary monoamines as well as

diamines and triamines.90 The degree of protonation was followed by determining the relative areas under the N 1s peaks at ∼399 eV (free amine) and at ∼401 eV (protonated or hydrogen-bonded amine).97 Several interesting trends were observed as a function of position along the gradient and with the specific aminosilane precursor employed. Some of the most interesting results are shown in Figure 5. These data demonstrate that the tertiary monoamine derived from N,N-diethylaminopropyltrimethoxysilane was the most

Figure 5. Ratio of areas under the N 1s XPS peaks at 401 and 399 eV for amine gradients incorporating mono-, di-, and triamine moieties. The inset plots the peak area ratio for the tertiary monoamine obtained in four replicate measurements along a single gradient. Reproduced from ref 90. Copyright 2012 American Chemical Society. E


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basic of the monoamines tested (i.e., exhibited the highest degree of protonation), the secondary monoamine, derived from N-butylaminopropyltrimethoxysilane came next, and the primary monoamine from aminopropyltrimethoxysilane was the least basic. The diamine and triamine groups derived from N-[3-(trimethoxysilyl)propyl] ethylenediamine and N-[3-(trimethoxysilyl)propyl] diethylenetriamine, respectively, were the least basic of all. Some of the gradients investigated showed variations in basicity with position. One such example is highlighted in the inset of Figure 5. In this case, the degree of protonation was found to decrease from the top of the gradient (∼0 mm, low amine end) to the bottom (∼16 mm, high amine end). This trend was best observed with the most basic tertiary monoamine. Indeed, Le Chatelier’s principle predicts that the degree of protonation should increase with decreasing amine concentration. Furthermore, as the density of protonated amine sites increases, the Kb of the remaining free amine sites is expected to decrease.99 The protonation of the amine sites may also involve the transfer of a proton from neighboring silanol groups. As the surface coverage of the aminosilane increases, the density of these weak acid sites will decrease, providing fewer protons to transfer to the amine groups. These results demonstrate the utility of gradient samples in studies of these and other concentration-dependent phenomena. Silane gradients are naturally charged due to the presence of weakly acidic silanol groups. Additional charge can be introduced by the incorporation of other acidic or basic functional groups along the gradient. A simple one-component gradient of amine groups prepared by depositing an organoalkoxysilane on a silica base layer would incorporate a gradient in amine groups and a counter gradient in silanol groups. More complex multicomponent gradients can be prepared by depositing two precursors, such as those incorporating amine and sulfonate groups, during gradient formation.87 In this case, the functional group densities can vary in either an aligned or opposed fashion. Once again, these films may incorporate a gradual gradient in silanol groups. The net charge on the surface of these gradients depends on the pH of the contacting solution, the surface density of each functional group, and the locations of these groups with respect to each other. These gradients provide a valuable system upon which to base the study of cooperative effects between neighboring functional groups. In recent work, aligned and opposed charge gradients consisting of surface-bound weak acids and bases have been prepared using CRI.87,100 The net charge on uniform samples prepared to mimic these gradients was deduced from streaming potential measurements of their zeta potentials. The results of these studies are shown in Figure 6 for samples characterized under solutions of different pH. The samples were prepared by dipping a TMOS-modified silicon wafer into sols derived from different mixtures of aminopropyltriethoxysilane (APTEOS) and mercaptopropyltrimethoxysilane (MPTMOS). The mercapto groups were subsequently oxidized to sulfonic acids by exposure to H2O2. The resulting surfaces incorporated RNH2, RSO3H, and SiOH groups, along with their corresponding conjugate weak acids and bases. Figure 6A shows the results obtained from samples that mimic an opposed gradient. The purple curves depict data from samples with a high density of RNH3+ groups and a low density of RSO3− groups. These yielded positive zeta potentials at low pH where RNH3+ groups determine the surface charge. As

Figure 6. Zeta potential as a function of pH for samples that mimic (A) opposed and (B−D) aligned amine-sulfonate gradients.87,100 The R values give the volume ratio R = RNH2/RSO3H. The zeta potential becomes independent of film composition at the point of intersection (POI) for materials that mimic aligned gradients.

expected, the zeta potentials decreased as the pH increased as a result of deprotonation of the silanol and ammonium groups. The red curves depict similar behavior for samples having a high density of RSO3− groups and a low density of RNH2 groups. In this case, the zeta potentials were significantly more negative but showed the same pH-dependent trend. The parallel zeta potential curves indicate that surface charge should decrease monotonically in the same direction regardless of position along opposed gradients. The samples mimicking aligned gradients (Figure 6B−D) produce more interesting results. In this case, both the RNH3+ and RSO3− group densities decrease together while the SiOH coverage increases. For each of the three sets of samples depicted, there is a particular pH that we call the point of intersection (POI) where the zeta potential is the same for all films. These results predict that the zeta potential of an aligned gradient would decrease monotonically in one direction along the gradient at pH < POI and in the opposite direction at pH > POI. Interestingly, at pH ≈ POI, the charge would be uniform across the surface and no charge gradient would exist at all. These results demonstrate that aligned weak acid/base gradients could be used to prepare pH-switchable charge gradients. By changing the relative densities of RNH3+ and RSO3− groups on the surface, both the pH and charge at the POI can be strategically altered.100 The samples shown in Figure 6B−D have approximately the same surface coverage of RNH3+ but gradually increasing amounts of RSO3−. The R values given in Figure 6B−D reflect the volume ratio R = RNH2/RSO3H F


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employed in sample preparation. As can be seen, the pH at the POI shifts to more basic values (6.4 → 7.3) and the zeta potential becomes increasingly positive as R increases. The origin of the unique pH switchability of aligned multicomponent charge gradients is found in acid−base chemical equilibria. Films that incorporate multiple ionizing species behave much like the ampholytes commonly used to establish pH gradients for isoelectric focusing.101,102 Effectively, the POI is similar to the isoelectric point except that the average charge is not exactly zero at the POI because of an imbalance in the coverage of cationic and anionic surface groups and differences in their hydrolysis constants. Wettability (Static and Dynamic Contact Angles/ Wilhelmy Plate Method). Gradient wettability data across millimeter length scales are commonly obtained from sessile drop water contact angle (WCA) measurements (Figure 4C).2 Unfortunately, this method allows only for discrete measurements of the WCA at specific locations. A more powerful approach that affords continuous WCA measurements and hence is better suited to gradient characterization is the Wilhelmy plate dynamic contact angle (WP-DCA) method. The only requirement for WP-DCA measurements is that the gradient must be present on both sides of the substrate. The WP-DCA method affords measurements of both the advancing, θadv, and receding, θrec, WCAs and hence gives the contact angle hysteresis (θΔ = θadv − θrec) as a function of position, allowing for the level of surface heterogeneity to be assessed.103−105 Elwing and Hlady first demonstrated its use as a tool for studying gradients in the 1990s.4,106−108 We have recently used the WP-DCA method to evaluate the wettability and microscopic heterogeneity of protonated amine gradients supported on base-layer-coated substrates of differing hydrophobicity.92 During gradient preparation by CRI, the rate of infusion was changed at three locations. The transition between these regions was easily observed in the DCA measurements. In contrast to data acquired on uniformly modified substrates, DCA profiles obtained along gradient films had a striking sigmoidal appearance, as shown in Figure 7. These same data reveal important differences in θΔ for gradient films prepared on the different base layers. Film Morphology and Organization (Atomic Force Microscopy). Ideally, multicomponent organosilane gradients would be composed of materials that are well mixed on molecular length scales, yielding films that gradually transition from being dominated by one component to another. In reality, gradient composition often varies in a more complex fashion because of the limited miscibility of the film components and/ or differences in their interactions with the substrate surface. Phase separation of the gradient components23 and/or dewetting from the substrate16 may occur under these circumstances. The extent to which phase separation and dewetting are manifested in the final gradients may be limited by silane reaction kinetics and thus is difficult to predict. Along with the resulting variations in gradient composition, corresponding variations in physical film properties (e.g., topography and mechanical characteristics) are also likely to appear on nanometer and larger length scales. These features may be readily detected and characterized by atomic force microscopy (AFM). Although AFM has been widely used to observe and explore phase-separation phenomena in nongradient organosilane109 and organothiol110 monolayers, in thicker sol−gel-derived organosilane films,111,112 and along thiol23 and polymer22,113

Figure 7. Dynamic contact angle−distance curves on (A) a uniformly modified NH3+ surface and (B, C) for two NH3+ gradients prepared on different base-layer-coated substrates. The gradients were prepared on TMOS- and C8-derived base layers, respectively. Initial contact of the substrate with water is indicated by the arrow. The hydrophilic end was immersed first. The same abscissa is used for all samples; the exact position for each varies by ∼±3 mm. Reproduced from ref 92. Copyright 2017 American Chemical Society.

gradients, it has not yet been broadly applied in studies of phase separation along organosilane-based chemical gradients. AFM has, however, been used to characterize the density of gold nanoparticles adsorbed on amine-terminated organosilane gradients68 and to determine the surface potential on pHtunable gradients.20 We have used AFM to monitor the density of gold nanoparticles adsorbed along multicomponent aligned and opposed amine/thiol and ammonium/sulfonate gradients87 and to characterize inhomogeneous water films condensed on gradient surfaces from the ambient laboratory atmosphere.74 Future AFM investigations of organosilane gradients promise to provide extensive new knowledge of their nanometer-tomicrometer physical and chemical characteristics. Mass Transport and Adsorption/Desorption (SingleMolecule Methods). Organosilanes can be used to prepare surfaces of controlled wettability, adhesion, or lubricity, surfaces that exhibit corrosion resistance, or specific chemical interactions for chemical sensing, catalysis, or chemical separations. In all such applications, the mass transport of reagents, analytes, or contaminants in or on the films is important to their functional characteristics. Chemical gradients provide a time-efficient means for exploring the influence of surface properties on mass transport rates and mechanisms. Optical single-molecule detection and tracking methods have been employed by the Higgins group to probe the mass transport dynamics and surface interactions of model analytes on silica gradients.96 Similar studies have been performed previously on nongradient silica materials, as covered in a recent reviews.114,115 In our initial study, we investigated the diffusion of single Nile Red molecules in thin-film gradients prepared from TMOS and methyltrimethoxysilane (MTMOS)G


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the organic content of the film increased. The mean diffusion coefficient of each of the mobile populations also increased with the film organic content. Molecular motion in these films was likely facilitated by viscous, liquidlike organosilane oligomers.116 The two mobile populations were attributed to the formation of phase-separated domains that were individually rich in silica and methyl-modified silica, respectively, for slowly and rapidly diffusing molecules. In subsequent studies, we investigated the mechanisms of mass transport on self-assembled monolayer gradients derived from octyltrichlorosilane (OTCS) and cyanopropyltrichlorosilane (CNTCS).74 These were deposited from the vapor phase to form opposed gradients.32,117 The diffusive motions of a perylene diimide dye were again followed at the single-molecule level as a function of ambient RH. Results of the full data analysis are given in Figure 10. A minority of molecules were

derived sols using IWDC.96 Initial characterization by FTIR mapping revealed that the desired gradient was obtained. Fluorescence videos of the aged, dried samples recorded under low relative humidity (RH) incorporated bright, round fluorescent spots attributable to emission from individual Nile Red molecules. Figure 8A shows a representative fluorescent

Figure 8. Single-molecule fluorescence video data obtained along an MTMOS−TMOS-derived gradient prepared by IWDC. (A) Representative video frame showing the fluorescent spots produced by emission from single Nile Red molecules. The video data were acquired near the silica end of the gradient. (B) Trajectories showing the motions of the individual molecules across the length of the same video. Reproduced from ref 96. Copyright 2011 American Chemical Society.

image of these samples. The videos obtained showed two distinct populations of molecules. One fraction comprised molecules that were either permanently adsorbed or otherwise entrapped on or in the films, and the remainder moved randomly in the field of view. Figure 8B shows the pathways (i.e., trajectories) these molecules followed. The trajectories were subsequently used to determine the apparent diffusion coefficient, D, for each molecule from its mean square displacement (MSD). Here, MSD = 2nDt, for which n is the dimensionality of motion and t is time. Representative histograms showing the single-molecule D values obtained along one gradient are given in Figure 9. The adsorbed/ entrapped molecules appear at D ≈ 0. Although the immobile population remained approximately constant across the gradient, the mobile molecules split into two distributions as

Figure 10. Analysis of mass transport phenomena for single molecules along a CN-to-C8 silane gradient prepared by vapor diffusion methods. (A) Mean fraction of single molecules determined to be mobile as a function of position and ambient RH. (B) Fraction of mobile molecules exhibiting desorption-mediated (Levy-like) diffusion, determined from single-molecule step size distributions. The solid lines plotted through all data have been appended to better depict the trends. Reproduced from ref 74. Copyright 2015 American Chemical Society.

found to be mobile at the hydrophobic (C8) end of the gradient and at low RH, but the majority was mobile at the hydrophilic (CN) end at high RH. As the ambient RH increased, the population of mobile molecules increased across the gradient. Increased mobility of the molecules was attributed to the formation of a layer of water condensed from the ambient atmosphere onto the gradient surface. Measurements of the apparent diffusion coefficient for the perylene diimide dye revealed a complex dependence on both position along the gradient and ambient RH. Detailed investigations of the distance traveled by each molecule from one video frame to the next were undertaken to explain this behavior. The step-size distributions obtained were consistent with normal Fickian diffusion at the CN end, while molecular motion followed a desorption-mediated (Levy-like)118 mechanism at the C8 end. The fraction of molecules exhibiting desorption-mediated motion is plotted vs position for high-RH conditions in Figure 10B.

Figure 9. Histograms depicting the apparent diffusion coefficients for Nile Red molecules as a function of position along a TMOS-MTMOSderived gradient. The results demonstrate the presence of an immobile population (peak near 0 μm2/s) and two populations of mobile molecules. The arrows point to the population of intermediate mobility. Reproduced from ref 96. Copyright 2011 American Chemical Society. H


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Polarity (Single-Molecule Spectroscopic Methods). We have also employed single-molecule methods as a means to explore the polarity properties (i.e., dielectric constant) of multicomponent organosilane gradients and to obtain evidence of component phase separation.89 In these studies, IWDC was employed to prepare gradients from TMOS and phenyltrimethoxysilane (PTMOS) sols. Evidence of gradient formation was obtained from sessile drop WCA measurements and from Raman mapping (Figure 4). Solvatochromic dye Nile Red119 was employed as a means to determine the local film dielectric constant.120 The Nile Red response to solvent mixtures of different dielectric constants was first calibrated in bulk fluorescence experiments. The dye was then loaded into the films at nanomolar concentrations, and its motions were followed by two-color single-molecule tracking. Fluorescence videos were acquired simultaneously in two spectral bands spanning 590 ± 20 and 640 ± 20 nm as the molecules diffused through the films. These data were used to determine the dye emission ratio, E = (I640 − I590)/(I640 + I590) where I590 and I640 represent single-molecule fluorescence signal levels in the two spectral bands. The local Clausius−Mossotti factor, CM = (ε − 1)/(2ε + 1), was subsequently determined from the E values.89 Here, ε represents the dielectric constant of the environment. Evidence of spatial variations in film polarity on the ∼100 nm length scale was obtained, as shown in Figure 11. Histograms prepared from these data revealed a

which we have been involved are highlighted in the sections below. Metal Ion Binding. Important applications of aminefunctionalized surfaces include the extraction of metal ions from solution and their separation by the formation of surfacebound chelation complexes.121 In applications such as these, the coordination of the metal ion depends upon the surface density of ligands. The formation of chelation gradients provides a simple means to investigate the dependence of metal ion binding on ligand density. In recent work, we employed XPS mapping to study the coordination of metal ions to gradients of surface-immobilized mono-, bi-, and tridentate ligands.91 These gradients were prepared by CRI from APTEOS, N-[3-(trimethoxysilyl)propyl] ethylenediamine (diamine), and N-[3-(trimethoxysilyl)propyl] diethylenetriamine (triamine) precursors. Figure 12 shows

Figure 12. N 1s to Zn 2p3/2 (top) and N 1s to Cu 2p3/2 (bottom) peak area ratio along diamine and triamine gradients after complexation with Zn2+ or Cu2+ ions. The data are plotted as a function of position from the low-amine end to the high-amine end. Reproduced from ref 91. Copyright 2014 American Chemical Society.

representative results on metal ion binding to the diamine and triamine surfaces. These gradients were characterized by XPS both before and after exposure to Cu2+ and Zn2+ from aqueous solution. In each case, XPS mapping confirmed the presence of the amine gradients and the binding of the metal ions. Metal ion binding was quantified by integrating the area beneath the Cu 2p and Zn 2p peaks. The results revealed that only the diamine and triamine ligands could efficiently bind the metal ions, whereas little or no metal binding occurred on the monoamine surface. These observations are most consistent with a cooperative mechanism (i.e., chelation) for metal ion binding. It is concluded that cooperative binding occurs only when the amine groups are in close proximity, as they are when incorporated on the same molecule. It may also indicate that the amine groups on the monoamine surface are simply too far apart to form stable chelation complexes, even at the highamine end of the gradient. The density of the bound metal ion was found to exhibit a complex dependence on both the identity and surface concentration of the immobilized chelator. As shown in Figure 12, the nitrogen to zinc metal ratio generally increased with increasing amine content. In contrast, the nitrogen to copper ratio remained approximately constant along the gradients.91 The origins of the complexities and differences between these samples are currently unknown.

Figure 11. Evidence of nanoscale phase separation in a PTMOS− TMOS-derived polarity gradient prepared by IWDC, as measured by single-molecule methods. (A) Representative trajectory showing the motions of a Nile Red single molecule on the gradient. (B) Polarity data for the same trajectory plotted as the emission ratio, E (left axis), and Clausius−Mossotti factor, CM (right axis). The molecule moved repeatedly between relatively nonpolar (red) and polar (green) domains. Reproduced from ref 89. Copyright 2014 American Chemical Society.

gradual shift in polarity from nonpolar environments at the high phenyl end to more polar materials at the low phenyl end. Interestingly, midway along the gradient, broad and/or bimodal distributions were obtained and were interpreted to reflect component phase separation on macroscopic length scales.

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EMERGING CONCEPTS AND NEW DEVELOPMENTS New applications of chemical gradients continue to be regularly reported in the literature. Three promising new directions in I


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Stationary-Phase Gradients for Liquid Chromatography. One promising and relatively new application of chemical gradients is in the field of liquid chromatography. To separate mixtures of molecules with widely varying polarities, gradient elution is often employed. In this method, the polarity of the mobile phase is changed during the course of a separation. An alternative paradigm involves changing the polarity of the stationary phase while maintaining a constant mobile-phase composition. We have recently explored the potential of stationary-phase-gradient chromatography using continuous gradients prepared by CRI methods.24−26,86 Our first studies involved the modification of high-performance thin-layer chromatography (TLC) plates with an APTEOS sol.24 We demonstrated that separations of a weak acid/base mixture and of three pharmaceuticals were improved on amine gradient TLC plates when compared to both unmodified and uniformly modified TLC plates. In more recent work, we showed how both aligned and opposed twocomponent phenyl and amine gradients, again prepared by CRI on TLC plates, could be used to separate a mixture of vitamins.86 Retention factors for the different vitamins were dependent on the spotting end and whether the individual gradients were aligned or opposed.86 Improved separations on continuous multicomponent gradients may arise from cooperative interactions that cannot be readily accessed with discontinuous gradients.25 In later studies, gradient TLC plates modified with mono-, di-, and triamine moieties were investigated for use in chelation chromatography separations of Co2+, Pb2+, Cu2+, and Fe3+.26 Only the diamine and triamine gradients afforded good separations, likely because of their ability to chelate the metals. The best separations were achieved on gradients prepared with a high concentration of the triamine ligand.26 The Collinson and Rutan groups have also demonstrated that amine gradient stationary phases can be formed on monolithic columns for use in liquid chromatography.25 In this work, a continuous stationary phase gradient was fabricated on in-house-synthesized columns by infusing an aminoalkoxysilane sol through the silica monolith using CRI, as shown in Figure 13. The retention factors obtained for benzoic acid and 3aminobenzoic acid on this stationary-phase gradient were significantly different from those on both unmodified silica

columns and those that were uniformly modified with the amine. DNA Elongation. The spontaneous transport of liquid droplets along synthetic wettability gradients was originally demonstrated by Chaudhury and Whitesides in 1992.32 Since that time, new applications of this phenomena have continued to be discovered. We have recently demonstrated that spontaneous droplet motion along certain chemical gradients can be used to elongate and align double-stranded DNA in a process commonly known as molecular combing.35 Figure 14

Figure 14. Histograms and fluorescent images (insets) showing the alignment and elongation of dye-labeled DNA deposited from a spontaneously moving water droplet on a hydrophobicity gradient. The images were acquired as a function of position across the droplet pathway at the hydrophobic end. A model for DNA deposition from the moving droplet is shown at the bottom. Reproduced from ref 35. Copyright 2016 American Chemical Society.

shows results obtained on a gradient prepared from OTCS deposited from the vapor phase. The long fluorescent streaks shown in the images are dye-labeled DNA molecules. DNA elongation and alignment were investigated as a function of gradient functionality and as a function of position along and across the gradient. The results showed that the highest density of elongated DNA and the greatest degree of elongation were obtained near the hydrophobic end of the gradient. The data in

Figure 13. Preparation of amine gradients and controls on an inhouse-synthesized silica monolith using CRI and their characterization by XPS (plot at lower left). The retention characteristics of a mixture of weak acids and bases were evaluated, and significant differences in retention factors were noted between the gradient columns (gradient bar) and either uniformly modified (solid green bar) or unmodified (solid white bar) columns (plot at lower right). Reproduced from ref 25. Copyright 2016 American Chemical Society. J


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Figure 14 show that the DNA molecules were elongated and aligned along the direction perpendicular to the droplet−air interface (see model in Figure 14), consistent with a surfacetension-driven mechanism for elongation. This application of gradients might find utility in disposable devices for DNA bar coding.122

Maryanne M. Collinson received a B.S. degree in chemistry and forensic science from the University of Central Florida in 1987 and a Ph.D. degree in analytical chemistry from North Carolina State University in 1992. She continued her studies as a postdoctoral research associate in Professor Mark Wightman’s laboratory at the University of North Carolina at Chapel Hill. Her academic career began at Kansas State University. She moved to Virginia Commonwealth University in 2005 and holds the rank of professor. Her research program lies at the interface of nanoscience, materials chemistry, and analytical chemistry with a particular focus on the fabrication and characterization of gradient materials and high-surfacearea nanoporous metal and metal alloys for chemical analysis.

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CONCLUSIONS AND OUTLOOK Organosilane precursors can be used to form a virtually limitless variety of synthetic gradients in thickness, porosity, wettability, dielectric constant, charge, acidity, and/or chemical composition. Whether obtained by well-known vaporphase32,72,117 or solution-phase4 diffusion or by emerging sol−gel methods,85,93 only a relatively limited variety of organosilane gradients have been prepared and characterized to date. Although many new types of gradients are certain to be reported in the coming years, much remains to be learned to achieve precise control over their properties and to realize their full potential. For example, the conditions under which continuous or discrete gradients are formed are different for each precursor mixture and are difficult to predict. A better understanding of how thermodynamic phase separation and its ancillary kinetic limitations94 govern the type of gradient formed would facilitate their broader implementation in a variety of applications. The consequences of phase separation in gradient materials also remain largely unexplored. For example, in gradients designed to serve as stationary phases for chemical separations, a separation may be facilitated by cooperative interactions. These are expected to occur on continuous gradients where the functional groups are mixed at the molecular level but may be absent on discrete gradients. Further studies designed to identify and quantify the occurrence of phase separation and cooperative interactions along sol−gel gradients would facilitate their use as a means to achieve enhanced material performance.

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Daniel A. Higgins received a B.A. in chemistry from St. Olaf College in 1988 and a Ph.D. in chemistry from the University of Wisconsin, Madison in 1993. Afterwards, he did postdoctoral research at the University of Minnesota. He has served on the chemistry faculty at Kansas State University (KSU) since 1996, where he currently holds the rank of Professor. His group employs optical microscopy and single-molecule fluorescence detection and tracking methods to probe the properties of chemical gradients and mesoporous silica materials on nanometer length scales. He and his group have published over 100 scientific manuscripts to date on these and other topics.

AUTHOR INFORMATION

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Corresponding Authors

ACKNOWLEDGMENTS We gratefully acknowledge the many students and collaborators who have contributed to this work as well as funding from the U.S. National Science Foundation (DMR-1404805, DMR1404898, CHE-0820945, and CHE-1609449) and the U.S. Department of Energy (DE-SC0002362).

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Maryanne M. Collinson: 0000-0001-6839-5334 Daniel A. Higgins: 0000-0002-8011-2648

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Notes

The authors declare no competing financial interest. Biographies

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Organosilane Chemical Gradients: Progress, Properties, and Promise

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