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Hydration-Shell Vibrational Spectroscopy Dor Ben-Amotz J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02742 • Publication Date (Web): 22 May 2019 Downloaded from http://pubs.acs.org on May 28, 2019

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Journal of the American Chemical Society

Hydration-Shell Vibrational Spectroscopy Dor Ben-Amotz Purdue University, Department of Chemistry, West Lafayette, IN KEYWORDS: Raman, Infrared, Vibration, Water, Aqueous, Hydration-Shell, Water-Mediated Interactions, Multivariate Curve Resolution (MCR), Self Modeling Curve Resolution (SMCR) ABSTRACT: Hydration-shell vibrational spectroscopy provides an experimental window into solute-induced water structure changes that mediate aqueous folding, binding, and self-assembly. Decomposition of measured Raman and infrared (IR) spectra of aqueous solutions using multivariate curve resolution (MCR) and related methods may be used to obtain solute-correlated (SC) spectra revealing solute-induced perturbations of water structure, such as changes in water hydrogen-bond strength, tetrahedral order, and the presence of dangling (non-hydrogen-bonded) OH groups. More generally, vibrational-MCR may be applied to both aqueous and non-aqueous solutions, including multicomponent mixtures, to quantify solvent-mediated interactions between oily, polar, and ionic solutes, in both dilute and crowded fluids. Combining vibrational-MCR with emerging theoretical modeling strategies promises synergetic advances in the predictive understanding of multi-scale self-assembly processes of both biological and technological interest.

INTRODUCTION In spite of the ubiquity and versatility of water as a solvent and biological medium,1-4 many of its deep secrets remain tantalizingly elusive.5-10 These include questions concerning solute-induced changes in water structure and their influence on water-mediated interactions, as well as their role in the formation of dynamic multi-scale assemblies composed of oily, polar, and ionic molecules. This perspective surveys recent advances in addressing such questions using vibrational multivariate-curve-resolution (Raman-MCR and IR-MCR) and related hydration-shell vibrational spectroscopic methods. In addition to providing a timely overview of this fruitful experimental landscape, this perspective also highlights recent theoretical developments that promise to significantly extend the structural, thermodynamic, and dynamic information obtainable from vibrational-MCR spectroscopy. The success stories described in this perspective point to a rich horizon of open questions and emergent phenomena pertaining to multi-component and crowded systems of biological and technological importance. The remainder of this perspective begins with an overview of vibrational-MCR and related hydration-shell spectroscopies (with additional information provided as Supporting Information, SI). Subsequent sub-sections describe recent advances in the application of vibrational-MCR to pure water and aqueous solutions, including studies that combine experimental and theoretical strategies to quantitatively address longstanding questions pertaining to the hydration and interactions of oily molecules dissolved in water, as well as dissolved gases and salts, such as methane, CO2, and ions ranging in size from protons to surfactants. These recent developments highlight the remarkable sensitivity and information content of hydration-shell vibrational spectroscopy as well as the synergetic benefits of combining experimental and theoretical modeling strategies to probe

increasingly complex multi-component solutions and selfassembling structures.

DISCUSSION Vibrational-MCR Spectroscopy. Vibration-MCR is essentially a difference spectroscopy that may be conveniently implemented using a matrix algebraic algorithm called selfmodeling curve resolution (SMCR).11,12 The resulting SMCR decomposition of the measured vibrational spectra of the pure solvent and solutions containing a solute of interest yields a solute-correlated (SC) spectrum revealing vibrational features arising both from the solute itself and from any solvent molecules that are perturbed by the solute. In other words, a SC spectrum is equivalent to the non-negative minimum-area difference between the solution and pure solvent spectra. Thus, any solvent features appearing in a SC spectrum necessarily arise from soluteinduced perturbations of the solvent. Since such perturbed solvent features are typically buried under large solvent bands in the input spectra, obtaining reliable SC spectra requires measuring vibrational spectra with exceptionally high signal-to-noise (>1000:1), readily obtainable in a few minutes using current spectrometer designs.13,14 The application of Raman-MCR as a solvation-shell spectroscopy was first introduced in 200815 and has recently been extended to IR-MCR by Poul Petersen and coworkers, using attenuated total-internal reflectance (ATR) IR spectroscopy.14 Although vibrational-MCR is most conveniently implemented using SCMR, other methods (including manual direct subtraction) may be used to obtain essentially identical SC spectra.12,16 SMCR is formally restricted to two-component spectral decompositions, but may readily be applied to samples containing multiple chemical components by treating one component in the mixture as the solute. This strategy is quite general, as any component in

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the mixture may be treated as the solute, and the resulting SC spectrum will in general contain features arising from the solute itself and its influence on the vibrational spectra of the surrounding solvent molecules. Thus, RamanMCR12,13,16-36 and IR-MCR14,32,34 have been applied to aqueous solutions with one13,16-21,25,27,28,31,33-37 or more12,2224,26,29,31,32 solutes, including solutions of sufficiently high concentration that solute-solute interactions significantly influence SC hydration-shell spectra,12,18,22,26,28-30,38 thus making it possible to quantify the associated watermediated interactions.12,18,22,28,38 Vibrational-MCR spectroscopy has much in common with some other vibrational decomposition methods. These include methods based on closely related non-negative least squares algorithms,39,40 as well a IR difference (and isotopic double-difference) spectroscopic strategies independently developed and extended by the groups of Stangret41-48 and Lindgren,42,49,50 building on earlier work by Mundy and Spedding (1973).51 Alternatively, a novel ratiometric detection strategy can in some cases be used to obtain hydrationshell spectra that are essentially identical to the SC spectra obtained using SMCR.52 Moreover, vibrational terahertz (THz) difference spectroscopy has been extensively used by the Havenith group53-58 and others59,60 to resolve lowfrequency IR hydration-shell spectra. Some of the interesting results obtained using the above methods are further described in the following sub-sections (as well as in the papers cited above, and references therein). Solvation-shell spectra obtained using all of the above methods are essentially equivalent to the corresponding SC spectra, or one of the associated family of spectra arising from the mathematical "rotational ambiguity" inherent in all MCR spectral decompositions.12,16,61 In essence, rotational ambiguity is equivalent to that associated with the location of the boundary between a solute's solvation-shell and the surrounding solvent molecules. In other words, the minimum area SC spectrum essentially pertains to the tightest solvation-shell boundary, while the other members of the family of rotation-ambiguity spectra pertain to extending the boundary farther out from the solute. However, it is important to note that the solvation-shell features appearing in the minimum area SC spectrum may either arise from a few highly perturbed solvent molecules or from a larger number of less strongly perturbed solvent molecules.16,62 Other members of the rotational-ambiguity family of solute-correlated spectra are equivalent to a linear combination of the pure solvent and the minimum area SC spectrum. This spectroscopic rotational-ambiguity may be resolved, for example, by making use of an experimental or simulation-based estimate of the number of water molecules in the first solvation-shell around a solute to reconstruct the full first solvation-shell spectrum from the experimental SC and solvent spectra.33,37 For aqueous solutions, this is more easily done using Raman-MCR than IR-MCR because water Raman cross sections are less sensitive to hydrogen-bond strength (and structure) than IR spectra, and thus one may assume that the Raman spectrum of the first hydration-shell has an area that is approximately equivalent to that pertaining to the corresponding number of first hydration-shell water molecules.33,37 See the SI for additional

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information regarding various implementations, capabilities, and limitations of vibrational-MCR. Pure water. Given that water is a single component system, it is not obvious how one might make use of vibrationalMCR to investigate its structure. However, there is a long history of interest in treating pure water as a mixture of two (or more) components.63-65 In the early literature, such two components models were sometimes associated with a mixture of hydrogen-bonded and non-hydrogen-bonded species. In the more recent literature, there have been some attempts to describe water as a mixture of "low density liquid" (LDL) and "high density liquid" (HDL) structures. The LDL structure is presumed to resemble a primarily tetrahedral (ice-like) structure with a coordination number of ~4 waters around each water, while the HDL structure is thought to have a coordination number closer to 5 with an extra water molecule from the 2nd hydration-shell intercalating into the tetrahedral 1st hydration-shell around each water molecule.66 On the other hand, spectral components obtained from cold and supercooled water Raman spectra have also been attributed to other types of high and low density structures, as well as ice.67 However, computer simulations (both classical and quantum) indicate that any two-component model of liquid water is, at best, a crude first approximation, as liquid water is composed of a broad continuum of structures68 with different hydrogen-bond lengths, angles, and coordination numbers, as well as chiral structures that are unlike those of any crystalline ice phase.69 Moreover, as elegantly demonstrated by Phil Geissler,68,70 such a continuum of structures may also give rise to two-state-like vibrational spectra, with an (approximate) isosbestic point at which the spectral intensity is nearly temperature independent, thus resembling a twocomponent mixture. Since water often mimics two-state behavior, one may use vibrational-MCR to determine the spectra associated with the two components. 67,71,72 When this was done using both the experimentally measured71 and theoretically predicted72 spectra of water, over a 280K to 360K temperature range (at ambient pressure), it was found that the resulting spectra could indeed be quite well described as a linear combination of two components, as shown in Figure 1. However, measurements of the spectrum of water over a larger temperature range, up to ~600K (at 30 MPa), 33 or down to ~250 K,67 reveal that the spectra no longer have an approximate isosbestic point, and thus can no longer be well approximated as a mixture of two components. Moreover, the above conclusions are consistent with both classical33,73 and quantum simulation results72,73 showing that other order parameters also display approximately two-state-like behavior over the ambient liquid temperature range of water, but not over a wider temperature range.


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Figure 1. Raman-MCR decomposition of the OH stretch band of water at 300K into high (dashed red) and low (dashed blue) disorder components.71 The high disorder (high temperature) component is equivalent to the measured spectrum of water at 360K, and the low disorder (low temperature) component is obtained from a global SMCR decomposition of the water spectrum from 280K360K. The 3200 cm-1 peak in the low temperature component is characteristic of a highly tetrahedral (ice-like) structure.

Another way in which vibrational-MCR may be used to obtain information about the structure and vibrational couplings in pure water is by making use of isotopic mixtures of H2O and D2O. If the isotopic species is sufficiently dilute, then the solution is essentially composed of HOD dissolved in either H2O or D2O. Some of the resulting HOD spectral features may readily be observed without making use of vibrational-MCR. These include, for example, the OH stretch band of HOD in D2O and the OD stretch band of HOD in H2O, both of which appear directly in the measured spectra. The fact that these isolated OH and OD bands look quite different from those of pure H2O or D2O, clearly points to the influence of intra- and/or inter-molecular vibrational coupling in liquid water. More detailed information regarding these couplings can be obtained by using vibrational-MCR to uncover information that is not readily evident in the measured spectra. For example, one may use Raman-MCR to obtain the SC OD stretch band of HOD in D2O, and the OH stretch band of HOD in H2O, both of which are buried under the solvent OD or OH bands, respectively. One might expect these HOD OH and OD bands to be identical to those that are not buried under the corresponding solvent band – but that is not the case. One possible reason for the difference could be the influence of intermolecular resonance coupling between the HOD OH band and the surrounding H2O OH groups, and thus vibrational-MCR could provide an opportunity to quantitatively distinguish intermolecular and intramolecular couplings in liquid water. The Raman-MCR of such isotopically dilute water mixtures74 are in fact qualitatively consistent with prior resonance coupling predictions by Yang and Skinner.74,75 However, the experimental results also make it clear that the situation is somewhat more complicated and interesting, as the Raman-MCR SC spectra of HOD in H2O, for example, have a larger intensity than expected if the spectra were entirely due to HOD. Thus, the RamanMCR results indicate that the SC spectra also include contributions from H2O molecules surrounding HOD, whose

structure is perturbed by HOD, and thus is not identical to the (average) structure of pure H2O.74 Other features of the observed Raman-MCR spectra remain to be explained, as they imply that intermolecular resonance coupling decreases the intensity of the HOD OD stretch in D2O but increases the intensity of the HOD OH stretch in H2O.74 Recent advances in theoretical strategies for predicting the structure and vibrational Raman,72,73 IR,73 and THz55,76 spectra of water imply that such calculations will become increasingly routine in the near future, and thus will become more broadly applicable to complex aqueous systems. For example, Francesco Paesani and coworkers have developed a many-body polarizable force field, based on high-level ab initio calculations of water clusters, and used it to predict the structure and vibrational spectra of liquid water.73,77 Tom Markland and his group have pursued an alternative strategy using fully quantum mechanical simulations (in which both the electronic and nuclear degrees of freedom of water are treated quantum mechanically) and shown that this strategy is also able to predict vibrational spectra in good agreement with experimental measurements.72,78 However, neither of the above vibrational spectroscopic calculation methodologies included the influence of intra-molecular Fermi-resonance coupling between the HOH bend overtone and OH stretch fundamental of water, which 2D-IR experiments have demonstrated to be significant.79,80 Fermi-resonance has long been suspected to contribute to intensity on the low frequency side of the OH stretch Raman band of water.71,77,81 This expectation has recently been confirmed theoretically by Kananenka and Skinner,82 who were the first to include Fermi-resonance coupling in the calculation of liquid water vibrational spectra. A prior study by Paesani and coworkers included Fermi-resonance in calculations of the IR spectra of water clusters.83 Hydrophobic Hydration. The influence of oily molecules on water structure has been a subject of longstanding interest and debate37 dating back at least to the seminal thermodynamic study by Frank and Evans,84 which postulated the formation of “frozen patches or microscopic icebergs" around oily solutes dissolved in water. However, no such icebergs are found in simulations of aqueous solutions (although water rotation is slowed around oily molecules)85,86. Sum frequency spectroscopy at oil-water interfaces has also found no evidence of ice-like structures, although an early SFG study concluded that interfacial water hydrogen bonds are weakened,87 while more recent measurements have found enhanced interfacial ordering and stronger hydrogenbonds,88 with SFG spectra that are quite similar to RamanMCR hydration-shell spectra of oily solutes dissolved in water. 13,25,33 Additionally, recent Raman-MCR37 and isotopic IR double difference89 studies of methane dissolved in liquid water have found that the first hydration-shell of methane is more tetrahedrally ordered than the surrounding liquid water at ambient (and lower) temperatures. Moreover, the Raman-MCR results revealed that above ~85°C methane's hydration-shell undergoes a crossover to a structure that is less tetrahedral than the surrounding bulk water, as shown in Figure 2.37 This crossover resembles that pre-



viously observed in aqueous solutions of alcohols,13,33 carboxylate anions,25 and alkylammonium cations25 of various chain lengths (as well as CO2)31, which may be related to prior theoretical size-dependent hydrophobic crossover (and "dewetting") predictions, as further discussed below.

Figure 2. Raman-MCR spectra of ~0.2 wt% methane in water reveal marked differences between pure water (dotted curves) and SC hydration-shell spectra (solid curves).37 Note in particular that with increasing temperature the average OH frequency in the hydration-shell crosses over from a lower to a higher frequency than bulk water.

The influence of the size of oily molecules on water structure has been a subject of much interest, beginning with early speculations by Kauzmann90 and scaled-particletheory-based arguments by Stillinger,91 leading to the more-recent "dewetting" predictions by Hummer and Garde92 and Lum, Chandler, and Weeks.93,94 The latter simulations pertain to idealized, purely repulsive (hardsphere) solutes, whose hydration-shells are predicted to undergo a crossover leading to the dramatic dewetting (vaporization) of the hydration-shells of hard-sphere solutes larger than ~1 nm in radius (at ambient temperature), with a critical crossover length-scale that decreases with increasing temperature.95,96 For more realistic oily solutes, attractive (van der Waals) solute-water interactions are predicted to suppress, but not entirely eliminate, the predicted sizedependent crossover behavior94 and its influence on hydration thermodynamics.97-99 Single-molecule polymer unfolding100 and Raman-MCR13 measurements have provided the first direct experimental evidence of size and temperature dependent crossover behavior.97,101 The spectroscopically observed structural crossover has also been linked to a dynamic crossover18 detectable using fsec-IR86,88 and NMR102,103 measurements of water rotational dynamics. Very recent Raman-MCR studies of aqueous alcohol solutions over an extended temperature range of -10°C to 374°C have confirmed the decrease in crossover lengthscale with increasing temperature.33 Moreover, comparisons of the Raman-MCR hydration-shell spectra of methane with that of methanol (and other alcohols) have revealed that the alcohol hydroxyl-group decreases both hydration-shell tetrahedrality and fragility.37 These results have gone a long way towards resolving longstanding questions, and apparent contradictions, between prior theoretical and experimental studies of hydrophobic hydration-

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shell structure. The bottom line is that the structure of water around oily molecules is extremely similar to that of bulk water, but undergoes a size- and temperature-dependent crossover from a slightly more tetrahedral structure at low temperatures to a more disordered structure at high temperatures, with a crossover temperature that decreases with increasing solute size. Intriguingly, these experimental results imply that the hydration-shell structural crossover for larger (polymeric or macromolecular) oily solutes should occur near ambient (or physiological) temperatures. A similar temperature dependent hydration-shell crossover has also been observed to occur around a CO2 dissolved in water,31 although it is not yet clear how this crossover is related to that observed around much larger oily solutes. A key difference between the two is that the Raman-MCR SC spectra of CO2 in both H2O and D2O reveal a prominent high frequency OH or OD band arising from a weak hydrogen-bond between water and on the slightly electronegative O atoms of CO2, as illustrated in Figure 3. Both the experimental and ab initio molecular dynamics (AIMD) simulation predictions indicate that an average of only ~20% of the CO2 molecules dissolved in liquid water accept one hydrogen-bond from water.31 This combined Raman-MCR and AIMD study was the first to definitively detect and quantify the weak hydrogen-bond between water and a dissolved CO2 molecule. Note that the formation of such a hydrogen bond may be viewed as introducing a defect in the hydrogen-bonded structure of water, and thus may contribute to the unusually low crossover temperature of the CO2 hydration-shell (near physiological temperatures).

Figure 3. Raman-MCR SC spectrum of CO2 in D2O. The assignment of the high frequency OD peak at ~2704 cm-1 to a weak hydrogen bond between D2O and CO2 is confirmed by AIMD calculations.31 A similar peak (at ~3654 cm-1) also appears in the hydration-shell of CO in H2O.31

A recent THz difference spectroscopic study of aqueous alcohol solutions (with various non-polar chain lengths and branching structures) included a detailed decomposition of the spectra into solute and solvent sub-group contributions.56 The results uncovered distinct low frequency subbands assigned to more ordered (tetrahedral) and less ordered (interstitial) water molecules. Correlations between spectroscopic and hydration-thermodynamic results led


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Martina Havenith and co-workers to conclude that temperature-dependent changes in the hydration heat capacity and free energy of alcohols are due primarily to the more disordered interstitial hydration-shell water molecules.56 Prior theoretical and experimental hydration thermodynamic analyses suggested that the characteristically large hydration heat capacities of non-polar solutes are linked to the associated hydration-shell structural crossover.95,104 Moreover, Raman-MCR of aqueous alcohols and other oily solutes of various sizes13 have found evidence of both high frequency non-hydrogen-bonded "dangling" OH species17,21 and enhanced tetrahedrality in hydration-shells of oily solutes.13 These Raman-MCR results further revealed a red-shift in the high-frequency edge of the hydration-shell OH stretch band, consistent with early molecular dynamics predictions that the hydration-shells of oily molecules have fewer weak (highly distorted) hydrogen-bonds than bulk water.105 Although it is not yet entirely clear how all the above puzzle pieces fit together, they contribute to the emergence of a more detailed picture of hydrophobic hydration than was possible without the aid of hydrationshell vibrational spectroscopy. Hydrophobic Interactions. The contact free energy between two (or more) oily molecules dissolved in water is determined by the corresponding potential of mean force (PMF) – which is equivalent to the reversible work associated with moving the oily molecules relative to each other. More specifically, the contact value of the PMF is equal to the free energy associated with bringing two solute molecules into direct contact with each other. Although such information is obtainable from molecular dynamics simulations, very few experimental studies have quantified contact free energies. For example, thermodynamic measurements (such as vapor pressures and solvation free energies) can be used to obtain the corresponding osmotic second virial coefficient, which is in turn related to integrals over the PMF.106,107 Although the sign and magnitude of osmotic second virial coefficient quantifies the net attraction or repulsion between a pair of solutes, it does not provide a measure of the contact free energy. However, recent studies have demonstrated that vibrational-MCR spectroscopy may be used to place quantitative experimental bounds on contact free energies. The basic idea underlying this experimental strategy is that the formation of a direct contact between two oily molecules is expected to expel some first hydration-shell water molecules and thus decrease the total number of perturbed water molecules around each solute. The resulting depletion in the SC hydration-shell OH band area (per solute) has been used to obtain a quantitative measure of contact free energy, ΔGC, as illustrated in Figure 4.28

Figure 4. Comparison of experimental Raman-MCR measurements (points) and lattice model predictions (curves) for the relationship between contact free energy, ΔGC, and aggregationinduced hydration-shell depletion in aqueous solutions containing methanol, tert-butyl alcohol (TBA), or butoxyethanol (BE) at 20°C.28

Each point in Figure 4 represents the hydration-shell depletion obtained from Raman-MCR measurements of the corresponding aqueous solutions, plotted as a function of the solute volume fraction. The dashed line and solid curves in Figure 4 were area lattice model predictions of the probability that the hydration-shell of a given solute will contain one (or more) other solute molecules.28,108 The dashed curve represents random mixing predictions in which the local (solvation-shell) solute concentration is equal to the bulk concentration. The solid curves are predictions obtained assuming different (negative) solute-solute contact energies. Although such lattice model predictions provide only a qualitative measure of the associated contact free energy, they make it quite clear that solutes such as methanol mix nearly randomly (and so have near zero contact free energy) while larger oily molecules such as tert-butyl alcohol (TBA) and butoxyethanol (BE) have negative contact free energies. More accurate estimates of the contact free energies may be obtained by performing more realistic random-mixing simulations, and linking those to the experimentally measured hydration-shell depletions, to quantify the excess number of solute-solute contacts (relative to a random mixture). Such analyses indicate that the contact free energy of TBA and BE are ΔGC ≈ -0.6±2 kJ/mol18 and ΔGC ≈ -3.0±0.4 kJ/mol,28 respectively. In spite of the significant experimental uncertainties, the results clearly indicate that the contact free energies between all these oily molecules are of the order of thermal energy RT ~ 2.5 kJ/mol, and become increasingly favorable as the size of the oily molecule increases.7,8 In order to quantify the water-mediated contribution to such contact free energies one must separate the contact free energy into water-mediated and solute-solute contributions. In other words, if the contact free energy in water is more negative than it would have been in the absence of water, that would imply a negative (attractive) watermediated interaction. Interestingly, when such an analysis is performed on oily molecules such as TBA and BE, the



associated water-mediated interaction is invariably found to be positive (repulsive), implying that water tends to pull these oily molecules apart rather than push them together.18,28 Further elucidating such water-mediated interaction free energies will undoubtedly require combined experimental and theoretical modeling studies to more accurately connect measured hydration-shell depletions with the number of direct (and water-separated) solute-solute contacts. Although the water-mediated interactions between nonpolar groups is relatively small, the fact that it is typically repulsive implies that the water shields the attractive van der Waals interaction between oily molecules. Thus, the widely held assumption that hydrophobic interactions are driven by the unfavorable oil-water interfacial free energy clearly requires reappraisal. Note that the water-induced shielding of van der Waals interactions is also observable in measurements of the force between macroscopic nonpolar interfaces, as the associated Hamaker constant is found to decrease (by about a factor of 10) when the gap between the two interfaces is filled with water.109 Polar Solutes. The hydration-shell spectra of polar and ionic solutes are typically quite different from those of nonpolar solutes.15,35,39,110 Notable exceptions include molecules such as the strongly quadrupolar CO231 and oily cations such as alkylammonium ions17,25 whose hydration-shell spectra look quite similar to those of oily solutes such as alcohols13,33 and methane.37 Moreover, when hydrationshell spectra of carboxylate anions are decomposed into contributions arising from the carboxylate head group and the non-polar tail, the hydration-shell of the non-polar tail is found to closely resemble that of neutral oily solutes.25 These results imply that the charged carboxylate head group only significantly influences the hydration-shell out to about the nearest alpha-methylene group. Interestingly, although aromatic groups are non-polar their hydrationshells are quite different from those of non-aromatic hydrocarbons. For example, the hydration-shells of benzene,19 phenol,19,23 pyridine,21 and tetraphenyl ions23 all contain a prominent high frequency OH peak assigned to a pihydrogen bond between water and the aromatic ring. However, the rest of the hydration-shell of such aromatic solutes has a structure that is remarkably similar to bulk water – much more so than the hydration-shells of saturated hydrocarbon rings such as cyclohexanol.19 A recent combined Raman-MCR and AIMD study of the hydration-shell of D-glucose110 found a blue-shift in the OH stretch peak frequency attributed to interstitial water molecules whose hydrogen bonded OH groups point out away from the solute. However, the Raman-MCR spectra also revealed a red-shift in the high frequency side of the OH stretch band, which was apparently not reproduced by the AIMD predictions. The latter red-shift is similar to that observed in prior Raman-MCR hydration-shell spectra of alcohols, attributed to the depletion of weak (distorted) hydrogen-bonded water molecules in the first hydrationshell of oily solutes.13,105 Another interesting recent Raman-MCR study by Jahur Mondal and coauthors compared hydration-shell spectra of

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polar cryoprotectants (DMSO and EG) and noncryoprotectants (acetone and dioxane).35 The results suggested that non-cryoprotectants disrupt the hydration-shell H-bonds to a greater extent than cryoprotectants. Mondal and coworkers have also used Raman-MCR to obtain ionic hydration-shell spectra111 which confirmed and extended earlier such studies indicating that cations such as Na+ have little effect on water structure, while anion hydration-shell spectra are very different from pure water with reduced inter- and/or intra-molecular coupling.20,111 An elegant early isotopic double-difference infrared spectroscopic study of aqueous acetonitrile (CH3CN), performed by Jamroz, Stangret, and Lindgren,42 concluded that there are fewer contacts between acetonitrile molecules in water than there would have been in a random mixture of acetonitriles of the same concentration, thus implying that both the contact free energy and water-mediated interaction free energy are positive for such strongly dipolar solute molecules. These results, when combined with results such as those shown in Figure 4, imply that water-mediated interactions between solutes become increasing repulsive with increasing solute polarity. The high solubility of salts such as NaCl in water provides an extreme example of repulsive water-mediated interactions, as the contact free energies between such ions in the absence of water have magnitudes of several hundred kJ/mol, while in water it is nearly zero (or at most of the order ~RT). Thus, water's ability to shield the electrostatic interaction between ions leads to a repulsive watermediated contribution to ion-pairing contact free energies of the order of hundreds of kJ/mol (positive). Such electrostatic shielding may well also contribute to the positive water-mediated interaction between aqueous acetonitrile molecules described above.42 The Hydrated Proton. The structure of a hydrated proton is a remarkably long-standing open question. Although chemistry textbooks typically describe protons in water as hydronium ions H3O+, the research literature has focused primarily on Zundel (H2O)…H+…(H2O) and Eigen H3O+(H2O)3 structures. Up until very recently, the consensus of opinion favored the Eigen-like structure as the predominant motif in acidic water, with the Zundel-like structures serving as proton-transfer transition states. However, recent 2D-IR studies of aqueous HCl112 and hydrated protons dissolved CH3CN113 suggested that Zundel-like structures are longer-lived and more abundant than previously thought. Moreover, a combined Raman-MCR, IR-MCR, and theoretical study provided strong evidence that protons in liquid water are primarily hydrated by two flanking water molecules,32 in general agreement with Zundel's extensive early spectroscopic studies.114 More specifically, the vibrational motion of the proton (which forms an exceptionally strong hydrogen-bond between the two water molecules) was found to have a very low frequency of ~1500±500 cm-1, consistent with its quantum mechanical delocalization along the associated barrierless potential energy surface, as shown in Figure 5. Most significantly, the proton's vibrational motion was found to be very strongly IR active and very weakly Raman active, thus


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clearly favoring its assignment to a Zundel-like rather than an Eigen-like structure. This combined experimental and theoretical study serves as a nice illustration of the usefulness of combining AIMD and anharmonic local-mode proton (and flanking water) vibrational frequency calculations in definitively assigning such vibration-MCR spectra.32

Figure 5. Hydrated proton AIMD simulation snap-shot and the associated proton potential energy vibrational quantum states, showing the O…H…O distance of 2.53 Å and proton vibrational frequency of 945 cm-1. The dashed red lines mark the first two vibrational quantum states of the proton and the blue curve is its delocalized ground state probability density.32

The above vibrational-MCR results also confirmed that there is little or no ion-pairing between the proton and its counter-anion (either Cl- or NO3-) below ~ 2M. This is consistent with earlier THz studies of aqueous HCl and HBr,58 although those earlier results were interpreted in terms of the prevailing view that protons have a predominantly Eigen-like structure. More generally, although it is increasingly clear that protons are primarily hydrated by two flanking water molecules in a Zundel-like structure, it is also evident there are very few perfectly symmetrical Zundel (or Eigen) species in liquid water.32 Ionic and Interfacial Interactions. The interaction between ions and both molecular and macroscopic interfaces is another subject of longstanding interest and debate. The importance of such interactions is evidenced in part by the fact that biological systems require both water and salt in order to function properly. Recent studies have demonstrated the utility of Raman-MCR as a means of quantifying ion hydration20,43 and ion-oil interactions,22,36,38 as well as the influence of counter-cations on the hydration-shell structure and mobility of OH- in water, interpreted with the aid of AIMD simulations and anharmonc vibrational frequency calculations.34 Early work by Onsager and Samaras115 predicted that all ions should be expelled from air-water and oil-water interfaces (because the dielectric constant of such interfaces is lower than that of water). However, more recent theoretical and experimental studies have found that competing entropic (cavity formation) contributions can lead to the preferential adsorption of some large ions, such as I-, at airwater interfaces.116,117 Although much effort has been de-

voted to quantifying the affinity of various ions for an airwater interface much less is known about the more biologically relevant interactions of ions with aqueous solutes, including oily molecules, and the influence of such interactions on binding and self-assembly. The penetration of an ion into the first hydration-shell of an oily molecule should perturb its hydration-shell spectrum as well as its CH stretch frequency. Thus, a recent study that combined Raman-MCR measurements and effective fragment potential based simulations and vibrational frequency calculations confirmed that while F- is strongly expelled from the hydration-shell of an oily TBA solute, larger polarizable I- ions penetrate significantly into the first hydration-shell of TBA.38 Subsequent Raman-MCR studies demonstrated that the concentration of both anions in the first hydration-shell of TBA is lower than the bulk concentration, although I- is significantly less strongly expelled from the hydration-shell than F-.22 Moreover, when TBA is replaced by a tetramethyl ammonium (TMA+) cation of similar size and shape, the concentration of I- in the first hydration-shell of TMA+ is found to increase but still not to significantly exceed the bulk I- concentration.38 These conclusions were confirmed and extended in subsequent Raman-MCR studies by the Mondal group.36 The dipolar and hydrogen bonding properties of water imply that water will interact quite differently with ions of opposite charge, and yet dielectric continuum models of water are symmetric with respect to solute charge. To quantify the influence of charge asymmetry it is convenient to make use of ion pairs such as the tetraphenylborate, B(C6H5)4- (TPB-), anion and tetraphynelarsonium, A(C6H5)4+ (TPA+), cation, which have nearly identical size and shape, but opposite charge. The Raman-MCR hydration-shell spectra of both TPB- and TPA+ contain an OH peak near 3600 cm-1 arising from water molecules pihydrogen bonded to the phenyl rings.23 However, the intensity of this peak is about 7 times larger for the TPB- than TPA+, indicating a significantly stronger pi-hydrogen-bond between water and TPB- than TPA+. This conclusion is supported by subsequent AIMD calculations,118 as well as prior isotopic IR measurements of the hydration-shell spectra of TPA- anion and tetraphenylphosphonium P(C6H5)4+ (TPP+) cation.43 Such tetraphenyl anions and cations have also been used to probe charge asymmetry in the adsorption of ions at airwater and oil-water interfaces. Surface selective vibrational sum frequency scattering (VSFS) studies have confirmed that the adsorbed anion and cation are associated with very different interfacial water structure changes at an oil-water interface.23 A subsequent surface sum frequency generation study of these ions at both air-water and oil-water interfaces concluded that the TPA+ cation has a greater interfacial affinity than the TPB- anion and the interfacial propensity obtained from vibrational sum frequency generation (SFG) spectroscopy differed from that inferred from thermodynamic surface tension measurements.119 The differential affinity of H+ and OH- for aqueous interfaces remains a hotly debated topic. On one hand, the measured electrophoretic mobilities of both oil drops and



air-bubbles in water have been interpreted as indicating that OH- is strongly adsorbed to both interfaces.120 On the other hand, VSFS121 and second harmonic generation (SHG)122 studies, as well as IR ion-exchange measurements and MD simulations,123 have reached the opposite conclusion, suggesting that H+ has a greater interfacial affinity than OH-. Another combined Raman-MCR and heterodyne-detected vibrational sum frequency generation (HD-VSFG) study obtained results suggesting that OH- influences the interfacial structure of aqueous alcohol solutions (of the same surface tension) in a way that is remarkably sensitive to both alcohol chain length and pH.124 However, a very recent combined VSFS and many-body molecular dynamics study found no evidence of the adsorption of either H+ or OH- at an air-water interface over a pH range of pH 2 to pH 11.125 Given the importance of both these ions in biology, it would be of interest to extend such studies to systems that include molecular interfaces of biological relevance. Many-Body Interactions. Simulations suggest that nonadditive many-body interactions are likely to influence aqueous folding, binding, and higher-order aggregation processes, and yet few experimental studies have directly probed such interactions. Recent detailed peptide and protein hydration free energy simulations have critically tested the validity of commonly invoked group additivity and surface area scaling assumptions and found that peptide hydration free energies are strongly influenced by non-local many-body interactions.126 In addition to questioning surface area scaling assumptions, these results also raise questions127 regarding Kauzmann's influential view90 that protein folding is driven primarily by hydrophobic interactions. Additionally, although some MD simulations suggest that the formation of small hydrophobic aggregates can be cooperative,128 other studies of high-order aggregation129 and oil nano-droplet coalescence7 indicate that such processes can be significantly anti-cooperative, in the sense that the total aggregation free energy is less favorable than the sum of the corresponding binary contact free energies. Although such predictions pertain to non-biological aggregation processes, they point to open questions regarding both the magnitude and sign of many-body contributions to the free energy driving force for biological (and other) multi-scale self-assembly processes. Recent studies illustrate how vibrational-MCR can provide a means of probing many-body interactions. For example, a Raman-MCR study of the aggregation of TBA in methanol-water mixtures provided solvation-shell spectroscopic evidence regarding the mechanism underlying "cononsolvency", in which the solubility in a mixture is lower than in either of the corresponding pure solvents.29 As another example, although it is often assumed that the collapse of hydrophobic polymers is preceded by dehydration (or some other change in hydration-shell structure), a recent RamanMCR study of the clouding aqueous PNIPAM polymer solutions found that the initially formed aggregates in a clouded PNIPAM solution remain nearly completely hydrated, prior to partial dehydration and disordering of the PNIPAM hydration-shell.30

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Recent Raman-MCR studies found that the interior of micelles composed of ionic surfactants remained significantly hydrated, and thus have structures that are inconsistent with classical spherical micelle models.26 Rather, the RamanMCR results suggest that such micelles contain wet nonpolar crevices or cavities whose depth increases with surfactant chain length.26 This implies that the oil-water interfacial tension in a micelle is much smaller (less unfavorable) than that of a macroscopic oil-water interface. It also implies that the structures of micelles have more in common with soluble proteins than implied by spherical micelle model predictions.130 It is interesting to consider the possible relationship between these results and those obtained using sum frequency scattering studies of surfactantstabilized oil nano-drops, which suggest that the saturated surface charge density of such nano-drops is about 5-10 times lower than that at a flat macroscopic surfactant stabilized oil-water interface.131,132 These results suggest that the structure of nano-scale assemblies can be strongly influenced by electrostatic interaction between charges on opposite sides of the oily core, and thus may also contribute to the non-spherical structure of micelles composed of ionic surfactants.

CONCLUSIONS AND OUTLOOK The results surveyed in this perspective illustrate how vibration-MCR experiments, combined with theoretical/simulation predictions, may be used to elucidate the structure of pure water and the hydration-shell of various solutes, as well as water-mediated interactions and shielding of both electrostatic and van der Waals interactions. Thus, vibrational-MCR measurements have confirmed theoretical predictions that the shielding of van der Waals interactions by water plays a major role in dictating the contact free energies between pairs of oily molecules dissolved in water.7,133,134 More generally, water's prodigious shielding ability, driven by a balance of solute-water and waterwater interactions renders ionic, polar, and oily solute molecules nearly invisible to each other up to concentrations above which there is not enough water to form a complete hydration-shell around each solute. It is under such highly crowded conditions, resembling those in the interior of living cells, that the delicate balance of water-mediated and ion-mediated interactions facilitates the emergence of chemically and mechanically responsive multi-scale structures. Many open questions remain regarding water-mediated interactions and their influence on biological folding, binding, aggregation, and self-assembly. Specifically, the coupling between water-mediated interactions and water structure and dynamics remains to be quantitatively elucidated. The challenges associated with addressing such questions are in part linked to an exact statistical thermodynamic relation, derivable from the Widom potential distribution theorem,135 which dictates that solute-induced changes in water-water interaction energy and entropy must strictly compensate.7,136,137 Thus, water's influence on the free energy driving force for any aqueous chemical process necessarily depends entirely on the direct interactions between the solute species with each other and with water, rather


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than on indirect solute-induced changes in water-water interaction energy and entropy. Thus, in seeking to quantify the influence of water structure on biological processes, one must focus on how changes in water structure influence solute-water interactions, rather than on whether or not a solute disrupts (or enhances) water-water interactions by, for example, decreasing (or increasing) the number of water-water hydrogen bonds. As a case in point, a recent course-grained protein folding study concluded that the stability of folded proteins is significantly influenced by "water’s density and energy fluctuations".138 However, the significance of this conclusion would be clarified if such calculations were extended to separately quantify the influence of water structure on the direct and indirect (strictly compensating) energetic and entropic contributions to protein-folding. Vibrational-MCR provides a means of experimentally probing solute-induced changes in water structure. In dilute solutions, these structure changes pertain to the hydration-shells of isolated solute molecules. The corresponding hydration-shell structures have been found to be strongly temperature dependent,13,31,33 but the influence of such changes on aggregation and self-assembly remains to determined. The same is true for influence of crowding on water-mediated and ion-mediated interactions, although the corresponding water structure changes are readily measurable using vibrational-MCR., Protein-ligand and other host-guest binding processes are undoubtedly influenced by binding-induced changes in water structure. For example, the displacement of “highenergy” water from a non-polar host cavity has been proposed as a driving force for supramolecular host-guest binding processes.62,139 However, a recently Raman-MCR study has found that water molecules inside a cyclodextrin cavity have a structure that is quite similar to liquid water, and pointed out that the competitive displacement of water by benzene cannot be driven by binding-induced changes in water-water interactions.140 Although vibrational-MCR spectra themselves can be quite informative, accurate theoretical/simulation predictions are often required in order to extract additional molecularly detailed information from vibrational-MCR measurements. The utility of such combined experimental and theoretical analysis strategies is illustrated, for example, by recent hydrated proton,32 hydroxide,34 CO2,31 and salt-oil interaction38 studies that have combined vibrational-MCR measurements with theoretical predictions to obtain a detailed picture of the associated hydration-shell structure. It would be useful to extend such studies to include the influence of various intra- and inter-molecular coupling mechanisms on the Raman and IR spectra of aqueous solutions. Moreover, recent predictions of the spectra of pure water using various more sophisticated methods72,73,82 imply that such strategies will soon be more routinely applicable to increasingly complex aqueous processes. Such synergetic combinations of experimental and theoretical strategies will undoubtedly continue to be fruitful in addressing the next level of questions regarding the influence of watermediated interactions and cooperativity on aqueous self-

assembly under biologically, geologically, and technologically relevant conditions. ASSOCIATED CONTENT Supporting Information Additional information regarding the capabilities and limitations of vibrational-MCR is provided as supporting information. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author * Dor Ben-Amotz, email: [email protected]

Author Contributions The manuscript was written by the author and includes summaries of work performed by many people (as described in the manuscript and references).

Funding Sources This work was supported by the National Science Foundation (CHE-109746).

ACKNOWLEDGMENT Contributions to the cited publications from numerous graduate and undergraduate students, postdoctoral fellows, visiting scientists, and collaborators, as well as studies carried out by other authors, are gratefully acknowledged.

ABBREVIATIONS MCR, multivariate curve resolution; SMCR, self-modeling curve resolution; SC, solute-correlated; IR, infrared; MD, molecular dynamics; AIMD, ab initio molecular dynamics; PMF, potential of mean force; VSFS, vibrational sum frequency spectroscopic; HD-VSFG, heterodyne-detected vibrational sum frequency generation; THz, terahertz; TBA, tert-butyl alcohol; BE, butoxyethanol; DMSO, dimethyl sulfoxide; EG, ethylene glycol; TPB-, tetraphenyl borate; TPA+ tetraphenyl ammonium; TPP+, tetraphyenyl phophonium.

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