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Cite This: J. Am. Chem. Soc. 2019, 141, 10569−10580 pubs.acs.org/JACS

Hydration-Shell Vibrational Spectroscopy Dor Ben-Amotz*

Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States

*S Supporting Information

molecules dissolved in , as well as dissolved gases and ABSTRACT: Hydration-shell vibrational spectroscopy salts, such as methane, CO2, and ranging in size from provides an experimental window into solute-induced protons to surfactants. These recent developments highlight water structure changes that mediate aqueous folding, the remarkable sensitivity and information content of binding, and self-assembly. Decomposition of measured hydration-shell vibrational spectroscopy as well as the Raman and infrared (IR) spectra of aqueous synergetic benefits of combining experimental and theoretical using multivariate curve resolution (MCR) and related modeling strategies to probe increasingly complex multi- methods may be used to obtain solute-correlated spectra component solutions and self-assembling structures. revealing solute-induced perturbations of water structure, such as changes in water hydrogen-bond strength, ■ DISCUSSION tetrahedral order, and the presence of dangling (non- hydrogen-bonded) OH groups. More generally, vibra- Vibrational-MCR Spectroscopy. Vibration-MCR is es- tional-MCR may be applied to both aqueous and sentially a difference spectroscopy that may be conveniently nonaqueous solutions, including multicomponent mix- implemented using a matrix algebraic algorithm called self- tures, to quantify -mediated interactions between modeling curve resolution (SMCR).11,12 The resulting SMCR oily, polar, and ionic solutes, in both dilute and crowded decomposition of the measured vibrational spectra of the pure fluids. Combining vibrational-MCR with emerging the- solvent and solutions containing a solute of interest yields a oretical modeling strategies promises synergetic advances solute-correlated (SC) spectrum revealing vibrational features in the predictive understanding of multiscale self-assembly arising both from the solute itself and from any solvent processes of both biological and technological interest. molecules that are perturbed by the solute. In other words, a SC spectrum is equivalent to the non-negative minimum-area difference between the and pure solvent spectra. Thus, ■ INTRODUCTION any solvent features appearing in a SC spectrum necessarily arise from solute-induced perturbations of the solvent. Since In spite of the ubiquity and versatility of water as a solvent and − such perturbed solvent features are typically buried under large biological medium,1 4 many of its deep secrets remain − solvent bands in the input spectra, obtaining reliable SC tantalizingly elusive.5 10 These include questions concerning spectra requires measuring vibrational spectra with exception- solute-induced changes in water structure and their influence ally high signal-to-noise (>1000:1), readily obtainable in a few on water-mediated interactions, as well as their role in the minutes using current spectrometer designs.13,14 Downloaded via PURDUE UNIV on July 20, 2019 at 17:57:01 (UTC). formation of dynamic multiscale assemblies composed of oily, The application of Raman-MCR as a -shell polar, and ionic molecules. This Perspective surveys recent spectroscopy was first introduced in 200815 and has recently advances in addressing such questions using vibrational been extended to IR-MCR by Poul Petersen and co-workers, multivariate-curve-resolution (Raman-MCR and infrared using attenuated total-internal reflectance (ATR) IR spectros- (IR)-MCR) and related hydration-shell vibrational spectro- 14 See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. scopic methods. In addition to providing a timely overview of copy. Although vibrational-MCR is most conveniently this fruitful experimental landscape, this Perspective also implemented using SCMR, other methods (including manual direct subtraction) may be used to obtain essentially identical highlights recent theoretical developments that promise to 12,16 extend significantly the structural, thermodynamic, and SC spectra. SMCR is formally restricted to two-component dynamic information obtainable from vibrational-MCR spec- spectral decompositions, but may readily be applied to samples troscopy. The success stories described in this Perspective containing multiple chemical components by treating one point to a rich horizon of open questions and emergent component in the mixture as the solute. This strategy is quite phenomena pertaining to multicomponent and crowded general, as any component in the mixture may be treated as the solute, and the resulting SC spectrum will in general contain systems of biological and technological importance. fl The remainder of this Perspective begins with an overview features arising from the solute itself and its in uence on the vibrational spectra of the surrounding solvent molecules. Thus, of vibrational-MCR and related hydration-shell spectroscopies − Raman-MCR12,13,16 36 and IR-MCR14,32,34 have been applied (with additional information provided as Supporting Informa- 13,16−21,25,27,28,31,33−37 tion, SI). Subsequent subsections describe recent advances in to aqueous solutions with one or 12,22−24,26,29,31,32 ffi the application of vibrational-MCR to pure water and aqueous more solutes, including solutions of su - solutions, including studies that combine experimental and theoretical strategies to quantitatively address longstanding Received: March 12, 2019 questions pertaining to the hydration and interactions of oily Published: May 22, 2019

© 2019 American Chemical Society 10569 DOI: 10.1021/jacs.9b02742 J. Am. Chem. Soc. 2019, 141, 10569−10580 Journal of the American Chemical Society Perspective ciently high concentration that solute−solute interactions (LDL) and “high density liquid” (HDL) structures. The LDL significantly influence the SC hydration-shell spec- structure is presumed to resemble a primarily tetrahedral (ice- − tra,12,18,22,26,28 30,38 thus making it possible to quantify the like) structure with a coordination number of ∼4 associated water-mediated interactions.12,18,22,28,38 around each water, while the HDL structure is thought to have Vibrational-MCR spectroscopy has much in common with a coordination number closer to 5 with an extra water some other vibrational decomposition methods. These include molecule from the second hydration-shell intercalating into the methods based on closely related non-negative least-squares tetrahedral first hydration-shell around each water molecule.66 algorithms,39,40 as well a IR difference (and isotopic double- On the other hand, spectral components obtained from cold difference) spectroscopic strategies independently developed and supercooled water Raman spectra have also been − and extended by the groups of Stangret41 48 and Lindg- attributed to other types of high and low density structures, ren,42,49,50 building on earlier work by Mundy and Spedding as well as ice.67 However, computer simulations (both classical (1973).51 Alternatively, a novel ratiometric detection strategy and quantum) indicate that any two-component model of can in some cases be used to obtain hydration-shell spectra liquid water is, at best, a crude first approximation, as liquid that are essentially identical to the SC spectra obtained using water is composed of a broad continuum of structures68 with SMCR.52 Moreover, vibrational terahertz (THz) difference different hydrogen-bond lengths, angles, and coordination spectroscopy has been extensively used by the Havenith numbers, as well as chiral structures that are unlike those of − group53 58 and others59,60 to resolve low-frequency IR any crystalline ice phase.69 Moreover, as elegantly demon- hydration-shell spectra. Some of the results obtained using strated by Phil Geissler,68,70 such a continuum of structures the above methods are further described in the following may also give rise to two-state-like vibrational spectra, with an subsections (as well as in the papers cited above, and (approximate) isosbestic point at which the spectral intensity is references therein). nearly temperature independent, thus resembling a two- Solvation-shell spectra obtained using all of the above component mixture. methods are essentially equivalent to the corresponding SC Since water often mimics two-state behavior, one may use spectra, or one of the associated family of spectra arising from vibrational-MCR to determine the spectra associated with the the mathematical “rotational ambiguity” inherent in all MCR two components.67,71,72 When this was done using both the spectral decompositions.12,16,61 In essence, rotational ambi- experimentally measured71 and theoretically predicted72 guity is equivalent to that associated with the location of the spectra of water, over a 280 to 360 K temperature range (at boundary between a solute’s solvation-shell and the surround- ambient pressure), it was found that the resulting spectra could ing solvent molecules. In other words, the minimum area SC indeed be quite well described as a linear combination of two spectrum essentially pertains to the tightest solvation-shell components, as shown in Figure 1. However, measurements of 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 33,37 Figure 1. Raman-MCR decomposition of the OH stretch band of experimental SC and solvent spectra. For aqueous water at 300 K into high (dashed red) and low (dashed blue) disorder solutions, this is more easily done using Raman-MCR than components.71 The high disorder (high temperature) component is IR-MCR because water Raman cross sections are less sensitive equivalent to the measured spectrum of water at 360 K, and the low to hydrogen-bond strength (and structure) than IR spectra, disorder (low temperature) component is obtained from a global and thus one may assume that the Raman spectrum of the first SMCR decomposition of the water spectrum from 280 to 360 K. The −1 hydration-shell has an area that is approximately equivalent to 3200 cm peak in the low temperature component is characteristic of that pertaining to the corresponding number of first hydration- a highly tetrahedral structure. shell water molecules.33,37 See the SI for additional information regarding various implementations, capabilities, and limitations of vibrational-MCR. the spectrum of water over a larger temperature range, up to Pure Water. Given that water is a single component ∼600 K (at 30 MPa),33 or down to ∼250 K,67 reveal that the system, it is not obvious how one might make use of spectra no longer have an approximate isosbestic point, and vibrational-MCR to investigate its structure. However, there is thus can no longer be well approximated as a mixture of two a long history of interest in treating pure water as a mixture of components. Moreover, the above conclusions are consistent − two (or more) components.63 65 In the early literature, such with both classical33,73 and quantum simulation results72,73 two components models were sometimes associated with a showing that other order parameters also display approx- mixture of hydrogen-bonded and non-hydrogen-bonded imately two-state-like behavior over the ambient liquid species. In the more recent literature, there have been some temperature range of water, but not over a wider temperature attempts to describe water as a mixture of “low density liquid” range.

10570 DOI: 10.1021/jacs.9b02742 J. Am. Chem. Soc. 2019, 141, 10569−10580 Journal of the American Chemical Society Perspective

Another way in which vibrational-MCR may be used to demonstrated to be significant.79,80 Fermi-resonance has long obtain information about the structure and vibrational been suspected to contribute to intensity on the low frequency couplings in pure water is by making use of isotopic mixtures side of the OH stretch Raman band of water.71,77,81 This ffi fi of H2O and D2O. If the isotopic species is su ciently dilute, expectation has recently been con rmed theoretically by then the solution is essentially composed of HOD dissolved in Kananenka and Skinner,82 who were the first to include either H2OorD2O. Some of the resulting HOD spectral Fermi-resonance coupling in the calculation of liquid water features may readily be observed without making use of vibrational spectra. A prior study by Paesani and co-workers vibrational-MCR. These include, for example, the OH stretch included Fermi-resonance in calculations of the IR spectra of 83 band of HOD in D2O and the OD stretch band of HOD in water clusters. fl H2O, both of which appear directly in the measured spectra. Hydrophobic Hydration. The in uence of oily molecules The fact that these isolated OH and OD bands look quite on water structure has been a subject of longstanding interest ff 37 di erent from those of pure H2OorD2O clearly points to the and debate dating back at least to the seminal thermody- influence of intra- and/or intermolecular vibrational coupling namic work of Frank and Evans,84 who postulated the in liquid water. More detailed information regarding these formation of “frozen patches or microscopic icebergs” around couplings can be obtained by using vibrational-MCR to oily solutes dissolved in water. However, no such icebergs are uncover information that is not readily evident in the measured found in simulations of aqueous solutions (although water spectra. For example, one may use Raman-MCR to obtain the rotation is slowed around oily molecules).85,86 Sum frequency SC OD stretch band of HOD in D2O, and the OH stretch spectroscopy at oil-water interfaces has also found no evidence band of HOD in H2O, both of which are buried under the of ice-like structures, although an early SFG study concluded solvent OD or OH bands, respectively. One might expect these that interfacial water hydrogen bonds are weakened,87 while HOD OH and OD bands to be identical to those that are not more recent measurements have found enhanced interfacial buried under the corresponding solvent band, but that is not ordering and stronger hydrogen-bonds,88 with SFG spectra the case. One possible reason for the difference could be the that are quite similar to Raman-MCR hydration-shell spectra of influence of intermolecular resonance coupling between the oily solutes dissolved in water.13,25,33 Additionally, recent 37 ff 89 HOD OH band and the surrounding H2O OH groups, and Raman-MCR and isotopic IR double di erence studies of thus vibrational-MCR could provide an opportunity to methane dissolved in liquid water have found that the first distinguish quantitatively intermolecular and intramolecular hydration-shell of methane is more tetrahedrally ordered than couplings in liquid water. The Raman-MCR of such isotopi- the surrounding liquid water at ambient (and lower) cally dilute water mixtures74 is in fact qualitatively consistent temperatures. Moreover, the Raman-MCR results revealed with prior resonance coupling predictions by Yang and that above ∼85 °C methane’s hydration-shell undergoes a Skinner.74,75 However, the experimental results also make it crossover to a structure that is less tetrahedral than the 37 clear that the situation is somewhat more complicated and surrounding bulk water, as shown in Figure 2. This crossover 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 Raman-MCR 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) 74 fi structure of pure H2O, as recently con rmed by Skinner and coworkers.141 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 74 HOD OH stretch in H2O. Recent advances in theoretical strategies for predicting the structure and vibrational Raman,72,73 IR,73 and THz55,76 Figure 2. Raman-MCR spectra of ∼0.2 wt % methane in water reveal spectra of water imply that such calculations will become ff increasingly routine in the near future, and thus will become marked di erences between pure water (dotted curves) and SC hydration-shell spectra (solid curves).37 Note in particular that with more broadly applicable to complex aqueous systems. For increasing temperature the average OH frequency in the hydration- example, Francesco Paesani and co-workers have developed a shell crosses over from a lower to a higher frequency than bulk water. 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 resembles that previously observed in aqueous solutions of Markland and his group have pursued an alternative strategy alcohols,13,33 carboxylate anions,25 and alkylammonium 25 31 using fully quantum mechanical simulations (in which both the cations of various chain lengths (as well as CO2), some electronic and nuclear degrees of freedom of water are treated of which may be related to prior theoretical size-dependent quantum mechanically) and shown that this strategy is also hydrophobic crossover (and “dewetting”)predictions,as able to predict vibrational spectra in good agreement with further discussed below. experimental measurements.72,78 However, neither of the The influence of the size of oily molecules on water structure above vibrational spectroscopic calculation methodologies has been a subject of much interest, beginning with early included the influence of intramolecular Fermi-resonance speculations by Kauzmann90 and scaled-particle-theory-based coupling between the HOH bend overtone and OH stretch arguments by Stillinger,91 leading to the more-recent fundamental of water, which 2D-IR experiments have “dewetting” predictions by Hummer and Garde92 and Lum,

10571 DOI: 10.1021/jacs.9b02742 J. Am. Chem. Soc. 2019, 141, 10569−10580 Journal of the American Chemical Society Perspective

Chandler, and Weeks.93,94 The latter simulations pertain to idealized, purely repulsive (hard-sphere) 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 size-dependent crossover behavior94 − and its influence on hydration thermodynamics.97 99 Single- molecule polymer unfolding100 and Raman-MCR13 measure- ments have provided the first direct experimental evidence of size and temperature dependent crossover behavior.97,101 The spectroscopically observed structural crossover has also been 18 86,88 Figure 3. Raman-MCR SC spectrum of CO2 in D2O. The assignment linked to a dynamic crossover detectable using fsec-IR ∼ −1 102,103 of the high frequency OD peak at 2704 cm to a weak hydrogen and NMR measurements of water rotational dynamics. fi 31 bond between D2O and CO2 is con rmed by AIMD calculations. A Recent Raman-MCR studies of aqueous alcohol solutions over similar peak (at ∼3654 cm−1) also appears in the hydration-shell of − ° 31 an extended temperature range of 10 to +374 C have CO in H2O. confirmed the decrease in crossover length-scale with 33 increasing temperature. Moreover, comparisons of the molecules. Correlations between spectroscopic and hydration- Raman-MCR hydration-shell spectra of methane with that of thermodynamic results led Martina Havenith and co-workers methanol (and other alcohols) have revealed that the alcohol to conclude that temperature-dependent changes in the hydroxyl-group decreases both hydration-shell tetrahedrality hydration heat capacity and free energy of alcohols are due 37 and fragility. These results have gone a long way toward primarily to the more disordered interstitial hydration-shell resolving longstanding questions, and apparent contradictions, water molecules.56 Prior theoretical and experimental hydra- between prior theoretical and experimental studies of hydro- tion thermodynamic analyses suggested that the characteristi- phobic hydration-shell structure. The bottom line is that the cally large hydration heat capacities of nonpolar solutes are structure of water around oily molecules is extremely similar to linked to the associated hydration-shell structural cross- that of bulk water, but undergoes a size- and temperature- over.95,104 Moreover, Raman-MCR of aqueous alcohols and dependent crossover from a slightly more tetrahedral structure other oily solutes of various sizes13 have found evidence of at low temperatures to a more disordered structure at high both high frequency non-hydrogen-bonded “dangling” OH temperatures, with a crossover temperature that decreases with species17,21 and enhanced tetrahedrality in hydration-shells of increasing solute size. Intriguingly, these experimental results oily solutes.13 These Raman-MCR results further revealed a imply that the hydration-shell structural crossover for larger red-shift in the high-frequency edge of the hydration-shell OH (polymeric or macromolecular) oily solutes should occur near stretch band, consistent with early ambient (or physiological) temperatures. predictions that the hydration-shells of oily molecules have A similar temperature dependent hydration-shell crossover fewer weak (highly distorted) hydrogen-bonds than bulk 105 has also been observed to occur around a CO2 dissolved in water. Although it is not yet entirely clear how all the above water,31 although it is not yet clear how this crossover is related puzzle pieces fit together, they contribute to the emergence of to that observed around much larger oily solutes. A key a more detailed picture of hydrophobic hydration than was difference between the two is that the Raman-MCR SC spectra possible without the aid of hydration-shell vibrational spec- of CO2 in both H2O and D2O reveal a prominent high troscopy. frequency OH or OD band arising from a weak hydrogen-bond Hydrophobic Interactions. The contact free energy between water and on the slightly electro-negative O atoms of between two (or more) oily molecules dissolved in water is CO2, as illustrated in Figure 3. Both the experimental and ab determined by the corresponding potential of mean force initio molecular dynamics (AIMD) simulation predictions (PMF), which is equivalent to the reversible work associated ∼ indicate that an average of only 20% of the CO2 molecules with moving the oily molecules relative to each other. More dissolved in liquid water accept one hydrogen-bond from specifically, the contact value of the PMF is equal to the free water.31 This combined Raman-MCR and AIMD study was energy associated with bringing two solute molecules into the first to definitively detect and quantify the weak hydrogen- direct contact with each other. Although such information is bond between water and a dissolved CO2 molecule. Note that obtainable from molecular dynamics simulations, very few the formation of such a may be viewed as experimental studies have quantified contact free energies. For introducing a defect in the hydrogen-bonded structure of example, thermodynamic measurements (such as vapor water, and thus may contribute to the unusually low crossover pressures and solvation free energies) can be used to obtain ffi temperature of the CO2 hydration-shell (near physiological the corresponding osmotic second virial coe cient, which is in temperatures). turn related to an integral over the PMF.106,107 Although the A recent THz difference spectroscopic study of aqueous sign and magnitude of the osmotic second virial coefficient alcohol solutions (with various nonpolar chain lengths and quantifies the net attraction or repulsion between a pair of branching structures) included a detailed decomposition of the solutes, it does not provide a measure of the contact free spectra into solute and solvent subgroup contributions.56 The energy. However, recent studies have demonstrated that results uncovered distinct low frequency sub-bands assigned to vibrational-MCR spectroscopy may be used to place more ordered (tetrahedral) and less ordered (interstitial) water quantitative experimental bounds on contact free energies.

10572 DOI: 10.1021/jacs.9b02742 J. Am. Chem. Soc. 2019, 141, 10569−10580 Journal of the American Chemical Society Perspective

The basic idea underlying this experimental strategy is that the it would have been in the absence of water, that would imply a formation of a direct contact between two oily molecules is negative (attractive) water-mediated interaction. Interestingly, expected to expel some first hydration-shell water molecules when such an analysis is performed on oily molecules such as and thus decrease the total number of perturbed water TBA and BE, the associated water-mediated interaction is molecules around each solute. The resulting depletion in the invariably found to be positive (repulsive), implying that water SC hydration-shell OH band area (per solute) has been used tends to pull these oily molecules apart rather than push them Δ 18,28 to obtain a quantitative measure of contact free energy, GC, together. Further elucidating such water-mediated inter- as illustrated in Figure 4.28 action 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 Figure 4. Comparison of experimental Raman-MCR measurements Polar Solutes. The hydration-shell spectra of polar and (points) and lattice model predictions (curves) for the relationship ff Δ ionic solutes are typically quite di erent from those of between the contact free energy, GC, and aggregation-induced nonpolar solutes.15,35,39,110 Notable exceptions include mole- hydration-shell depletion in aqueous solutions containing methanol, 31 tert-butyl alcohol (TBA), or butoxyethanol (BE) at 20 °C.28 cules such as the strongly quadrupolar CO2 and oily cations such as alkylammonium ions17,25 whose hydration-shell spectra look quite similar to those of oily solutes such as alcohols13,33 37 Each point in Figure 4 represents the hydration-shell and methane. Moreover, when hydration-shell spectra of depletion obtained from Raman-MCR measurements of the carboxylate anions are decomposed into contributions arising corresponding aqueous solutions, plotted as a function of the from the carboxylate headgroup and the nonpolar tail, the solute volume fraction. The dashed line and solid curves in hydration-shell of the nonpolar tail is found to closely resemble 25 Figure 4 are lattice model predictions of the probability that that of neutral oily solutes. These results imply that the the hydration-shell of a given solute will contain one (or more) charged carboxylate headgroup only significantly influences the other solute molecules.28,108 The dashed curve represents hydration-shell out to about the nearest α-methylene group. random mixing predictions in which the local (solvation-shell) Interestingly, although aromatic groups are nonpolar their solute concentration is equal to its bulk concentration. The hydration-shells are quite different from those of nonaromatic solid curves are predictions obtained assuming different hydrocarbons. For example, the hydration-shells of benzene,19 (negative) solute−solute contact energies. Although such phenol,19,23 pyridine,21 and tetraphenyl ions23 all contain a lattice model predictions provide only a qualitative measure prominent high frequency OH peak assigned to a π-hydrogen of the associated contact free energy, they make it quite clear bond between water and the aromatic ring. However, the rest that solutes such as methanol mix nearly randomly (and so of the hydration-shell of such aromatic solutes has a structure have near zero contact free energy) while larger oily molecules that is remarkably similar to bulk water, much more so than such as tert-butyl alcohol (TBA) and butoxyethanol (BE) have the hydration-shells of saturated hydrocarbon rings such as negative contact free energies. More accurate estimates of the cyclohexanol.19 contact free energies may be obtained by performing more A recent combined Raman-MCR and AIMD study of the 110 realistic random-mixing simulations, and linking those to the hydration-shell of D-glucose found a blue-shift in the OH experimentally measured hydration-shell depletions, to quanti- stretch peak frequency attributed to interstitial water molecules fy the excess number of solute−solute contacts (relative to a whose hydrogen bonded OH groups point out away from the random mixture). Such analyses indicate that the contact free solute. However, the Raman-MCR spectra also revealed a red- Δ ≈− ± 18 energy of TBA and BE are GC 0.6 2 kJ/mol and shift in the high frequency side of the OH stretch band, which Δ ≈− ± 28 GC 3.0 0.4 kJ/mol, respectively. In spite of the was apparently not reproduced by the AIMD predictions. The significant experimental uncertainties, the results clearly latter red-shift is similar to that observed in prior Raman-MCR indicate that the contact free energies between these oily hydration-shell spectra of alcohols, attributed to the depletion molecules are of the order of thermal energy RT ∼ 2.5 kJ/mol, of weak (distorted) hydrogen-bonded water molecules in the and become increasingly favorable as the size of the oily first hydration-shell of oily solutes.13,105 molecule increases.7,8 Another interesting recent Raman-MCR study by Jahur In order to quantify the water-mediated contribution to such Mondal and coauthors compared hydration-shell spectra of contact free energies one must separate the contact free energy polar cryoprotectants (DMSO and EG) and noncryoprotec- into water-mediated and solute−solute contributions. In other tants (acetone and dioxane).35 The results suggested that words, if the contact free energy in water is more negative than noncryoprotectants disrupt the hydration-shell H-bonds to a

10573 DOI: 10.1021/jacs.9b02742 J. Am. Chem. Soc. 2019, 141, 10569−10580 Journal of the American Chemical Society Perspective greater extent than cryoprotectants. Mondal and co-workers 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 intramolecular coupling.20,111 An elegant early isotopic double-difference infrared spectro- scopic 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 Figure 5. Hydrated proton AIMD simulation snapshot and the associated proton potential energy for this configuration with an O··· solutes become increasing repulsive with increasing solute H···O distance of 2.53 Å and proton vibrational frequency of 945 polarity. cm−1. The dashed red lines mark the first two vibrational quantum The high of salts such as NaCl in water provides states of the proton and the blue curve is its delocalized ground state an extreme example of repulsive water-mediated interactions, probability density.32 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, structural, dynamic, and spectroscopic properties of acidic 142 water’s ability to shield the electrostatic interaction between water. fi ions leads to a repulsive water-mediated contribution to - The above vibrational-MCR results also con rmed that pairing contact free energies of the order of hundreds of kJ/ there is little or no ion-pairing between the proton and its − − ∼ counteranion (either Cl or NO3 ) below 2M. This is mol (positive). Such electrostatic shielding may well also 58 contribute to the positive water-mediated interaction between consistent with earlier THz studies of aqueous HCl and HBr, aqueous acetonitrile molecules described above.42 although those earlier results were interpreted in terms of the Hydrated Proton. The structure of a hydrated proton is a prevailing view that protons have a predominantly Eigen-like structure. More generally, although it is increasingly clear that remarkably long-standing open question. Although chemistry fl textbooks typically describe protons in water as protons are primarily hydrated by two anking water molecules + in a Zundel-like structure, it is also evident there are very few ions H3O , the research literature has focused primarily on ··· +··· + perfectly symmetrical Zundel (or Eigen) species in liquid Zundel (H2O) H (H2O) and Eigen H3O (H2O)3 struc- 32 tures. Until very recently, the consensus of opinion favored the water. Ionic and Interfacial Interactions. The interaction Eigen-like structure as the predominant motif in acidic water, between ions and both molecular and macroscopic interfaces with the Zundel-like structures serving as proton-transfer is another subject of longstanding interest and debate. The transition states. However, recent 2D-IR studies of aqueous importance of such interactions is evidenced in part by the fact HCl112 and hydrated protons dissolved CH CN113 suggested 3 that biological systems require both water and salt in order to that Zundel-like structures are longer-lived and more abundant function properly. Recent studies have demonstrated the utility than previously thought. Moreover, a combined Raman-MCR, of Raman-MCR as a means of quantifying ion hydration20,43 IR-MCR, and theoretical study provided strong evidence that − 22,36,38 fl fl and ion oil interactions, as well as the in uence of protons in liquid water are primarily hydrated by two anking counter-ion pairing on the hydration-shell structure and water molecules,32 in general agreement with Zundel’s − 114 fi mobility of OH in water, interpreted with the aid of AIMD extensive early spectroscopic studies. More speci cally, the simulations and anharmonc vibrational frequency calcula- vibrational motion of the proton (which forms an exceptionally tions.34 strong hydrogen-bond between the two water molecules) was Early work by Onsager and Samaras115 predicted that all ∼ ± −1 found to have a very low frequency of 1500 500 cm , ions should be expelled from air−water and oil−water consistent with its quantum mechanical delocalization along interfaces (because the dielectric constant of such interfaces the associated barrierless potential energy surface, as is lower than that of water). However, more recent theoretical fi fi ’ exempli ed in Figure 5. Most signi cantly, the proton s and experimental studies have found that competing energetic vibrational motion was found to be very strongly IR active and entropic (cavity formation) contributions can lead to the and very weakly Raman active, thus clearly favoring its preferential adsorption of some large ions, such as I−, at air− assignment to a Zundel-like rather than an Eigen-like structure. water interfaces.116,117 Although much effort has been devoted This combined experimental and theoretical study serves as a to quantifying the affinity of various ions for an air−water nice illustration of the usefulness of combining AIMD and interface, much less is known about the more biologically anharmonic local-mode proton (and flanking water) vibra- relevant interactions of ions with aqueous solutes, including tional frequency calculations in definitively assigning such oily molecules, and the influence of such interactions on vibration-MCR spectra.32 As an alternative strategy, Tom binding and self-assembly. Markland and coworkers have recently used fully quantum The penetration of an ion into the first hydration-shell of an mechanical simulations to obtain detailed predictions of the oily molecule should perturb its hydration-shell spectrum as

10574 DOI: 10.1021/jacs.9b02742 J. Am. Chem. Soc. 2019, 141, 10569−10580 Journal of the American Chemical Society Perspective well as its CH stretch frequency. Thus, a recent study that body molecular dynamics study found no evidence of the combined Raman-MCR measurements and effective fragment adsorption of either H+ or OH− at an air−water interface over potential based simulations and vibrational frequency calcu- a pH range of 2 to 11.125 Given the importance of both these lations confirmed that while F− is strongly expelled from the ions in biology, it would be of interest to extend such studies to hydration-shell of an oily TBA solute, larger polarizable I− ions systems that include molecular interfaces of biological penetrate significantly into the first hydration-shell of TBA.38 relevance. Subsequent Raman-MCR studies demonstrated that the Many-Body Interactions. Simulations suggest that non- concentration of both anions in the first hydration-shell of additive many-body interactions are likely to influence aqueous TBA is lower than the bulk concentration, although I− is folding, binding, and higher-order aggregation processes, and significantly less strongly expelled from the hydration-shell yet few experimental studies have directly probed such than F−.22 Moreover, when TBA is replaced by a interactions. Recent detailed peptide and hydration tetramethylammonium (TMA+) cation of similar size and free energy simulations have critically tested the validity of shape, the concentration of I− in the first hydration-shell of commonly invoked group additivity and surface area scaling TMA+ is found to increase but still not to significantly exceed assumptions and found that peptide hydration free energies are the bulk I− concentration.38 These conclusions were confirmed strongly influenced by nonlocal many-body interactions.126 In and extended in subsequent Raman-MCR studies by the addition to questioning surface area scaling assumptions, these Mondal group.36 results also raise questions127 regarding Kauzmann’sinfluential The dipolar and hydrogen bonding properties of water imply view90 that protein folding is driven primarily by hydrophobic that water will interact quite differently with ions of opposite interactions. Additionally, although some MD simulations charge, and yet dielectric continuum models of water are suggest that the formation of small hydrophobic aggregates can symmetric with respect to solute charge. To quantify the be cooperative,128 other studies of high-order aggregation129 influence of charge asymmetry it is convenient to make use of and oil nanodroplet coalescence7 indicate that such processes − − fi ion pairs such as the tetraphenylborate, B(C6H5)4 (TPB ), can be signi cantly anticooperative, in the sense that the total + + anion and tetraphenylarsonium, As(C6H5)4 (TPA ), cation, aggregation free energy is less favorable than the sum of the which have nearly identical size and shape, but opposite corresponding binary contact free energies. Although such charge. The Raman-MCR hydration-shell spectra of both predictions pertain to nonbiological aggregation processes, TPB− and TPA+ contain an OH peak near 3600 cm−1 arising they point to open questions regarding both the magnitude from water molecules π-hydrogen bonded to the phenyl and sign of many-body contributions to the free energy driving rings.23 However, the intensity of this peak is about 7 times force for biological (and other) multiscale self-assembly larger for the TPB− than TPA+, indicating a significantly processes. stronger π-hydrogen-bond between water and TPB− than Recent studies illustrate how vibrational-MCR can provide a TPA+. This conclusion is supported by subsequent AIMD means of probing many-body interactions. For example, a calculations,118 as well as prior isotopic IR measurements of Raman-MCR study of the aggregation of TBA in methanol− the hydration-shell spectra of TPA− anion and tetraphenyl- water mixtures provided solvation-shell spectroscopic evidence + + 43 “ ” phosphonium P(C6H5)4 (TPP ) cation. regarding the mechanism underlying cononsolvency ,in Such tetraphenyl anions and cations have also been used to which the solubility in a mixture is lower than in either of probe charge asymmetry in the adsorption of ions at air−water the corresponding pure .29 As another example, and oil−water interfaces. Surface selective vibrational sum although it is often assumed that the collapse of hydrophobic frequency scattering (VSFS) studies have confirmed that the polymers is preceded by dehydration (or some other change in adsorbed anion and cation are associated with very different hydration-shell structure), a recent Raman-MCR study of interfacial water structure changes at an oil−water interface.23 aqueous PNIPAM found that the initially formed polymer A subsequent surface sum frequency generation study of these aggregates in a clouded PNIPAM solution remain nearly ions at both air−water and oil−water interfaces concluded that completely hydrated, prior to partial dehydration and disorder- the TPA+ cation has a greater interfacial affinity than the TPB− ing of the PNIPAM hydration-shell.30 anion and the interfacial propensity obtained from vibrational Recent Raman-MCR studies found that the interior of sum frequency generation (SFG) spectroscopy differed from micelles composed of ionic surfactants remained significantly that inferred from thermodynamic surface tension measure- hydrated, and thus have structures that are inconsistent with ments.119 classical spherical micelle models.26 Rather, the Raman-MCR The differential affinity of H+ and OH− for aqueous results suggest that such micelles contain wet nonpolar crevices interfaces remains a subject of heated debate. On one hand, or cavities whose depth increases with surfactant chain the measured electrophoretic mobilities of both oil drops and length.26 This implies that the oil−water interfacial tension air-bubbles in water have been interpreted as indicating that in a micelle is much smaller (less unfavorable) than that of a OH− is strongly adsorbed to both interfaces.120 On the other macroscopic oil−water interface. It also implies that the hand, VSFS121 and second harmonic generation (SHG)122 structures of micelles have more in common with soluble studies, as well as IR ion-exchange measurements and MD than implied by spherical micelle model predic- simulations,123 have reached the opposite conclusion, suggest- tions.130 It is interesting to consider the possible relationship ing that H+ has a greater interfacial affinity than OH−. Another between these results and those obtained using sum frequency combined Raman-MCR and heterodyne-detected vibrational scattering studies of surfactant-stabilized oil nanodrops, which sum frequency generation (HD-VSFG) study obtained results indicate that the saturated surface charge density of such suggesting that OH− influences the interfacial structure of nanodrops is about 5−10 times lower than that at a flat aqueous alcohol solutions (of the same surface tension) in a macroscopic surfactant stabilized oil−water interface.131,132 way that is remarkably sensitive to both alcohol chain length These results suggest that the structure of nanoscale assemblies and pH.124 However, a very recent combined VSFS and many- can be strongly influenced by electrostatic interaction between

10575 DOI: 10.1021/jacs.9b02742 J. Am. Chem. Soc. 2019, 141, 10569−10580 Journal of the American Chemical Society Perspective charges on opposite sides of the oily core, and thus may also corresponding water structure changes are readily measurable contribute to the nonspherical structure of micelles composed using vibrational-MCR. of ionic surfactants. Protein−ligand and other host−guest binding processes are undoubtedly influenced by binding-induced changes in the ■ CONCLUSIONS AND OUTLOOK water structure. For example, the displacement of “high- ” The results surveyed in this Perspective illustrate how energy water from a nonpolar host cavity has been proposed as a driving force for supramolecular host−guest binding vibration-MCR experiments, combined with theoretical/ 62,139 simulation predictions, may be used to elucidate the structure processes. However, a recent Raman-MCR study has of pure water and the hydration-shell of various solutes, as well found that water molecules inside a cyclodextrin cavity have a as water-mediated interactions and shielding of both electro- structure that is quite similar to liquid water, and pointed out static and van der Waals interactions. Thus, vibrational-MCR that the competitive displacement of water by benzene cannot fi be driven by binding-induced changes in water−water measurements have con rmed theoretical predictions that the 140 shielding of van der Waals interactions by water plays a major interactions. role in dictating the contact free energies between pairs of oily Although vibrational-MCR spectra themselves can be quite molecules dissolved in water.7,133,134 More generally, water’s informative, accurate theoretical/simulation predictions are prodigious shielding ability, driven by a balance of solute-water often required in order to extract additional molecularly and water−water interactions renders ionic, polar, and oily detailed information from vibrational-MCR measurements. solute molecules nearly invisible to each other up to The utility of such combined experimental and theoretical concentrations above which there is not enough water to analysis strategies is illustrated, for example, by recent hydrated 32 34 31 − 38 form a complete hydration-shell around each solute. It is under proton, hydroxide, CO2, and salt oil interaction such highly crowded conditions, resembling those in the studies that have combined vibrational-MCR measurements interior of living cells, that the delicate balance of water- with theoretical predictions to obtain a detailed picture of the mediated and ion-mediated interactions facilitates the associated hydration-shell structure. It would be useful to fl emergence of chemically and mechanically responsive multi- extend such studies to include the in uence of various intra- scale structures. and intermolecular coupling mechanisms on the Raman and IR Many open questions remain regarding water-mediated spectra of aqueous solutions. Moreover, recent predictions of fl the spectra of pure water using various more sophisticated interactions and their in uence on biological folding, binding, 72,73,82 aggregation, and self-assembly. Specifically, the coupling methods imply that such strategies will soon be more between water-mediated interactions and water structure and routinely applicable to increasingly complex aqueous processes. dynamics remains to be quantitatively elucidated. The Such synergetic combinations of experimental and theoretical challenges associated with addressing such questions are in strategies will undoubtedly continue to be fruitful in addressing fl part linked to an exact statistical thermodynamic relation, the next level of questions regarding the in uence of water- derivable from the Widom potential distribution theorem,135 mediated interactions and cooperativity on aqueous self- which dictates that solute-induced changes in water−water assembly under biologically, geologically, and technologically interaction energy and entropy must strictly compen- relevant conditions. sate.7,136,137 Thus, water’sinfluence on the free energy driving force for any aqueous self-assembly necessarily depends ■ ASSOCIATED CONTENT entirely on the direct interactions between the solute species *S Supporting Information with each other and with water, rather than on indirect solute- The Supporting Information is available free of charge on the induced changes in water−water interaction energy and ACS Publications website at DOI: 10.1021/jacs.9b02742. entropy. Thus, in seeking to quantify the influence of water Additional information regarding the capabilities and structure on biological processes, one must focus on how limitations of vibrational-MCR (PDF) changes in water structure influence solute-water interactions, rather than on whether or not a solute disrupts (or enhances) ■ AUTHOR INFORMATION water−water interactions by, for example, decreasing (or − Corresponding Author increasing) the number of water water hydrogen bonds. As a *Dor Ben-Amotz, email: [email protected] case in point, a recent course-grained protein folding study concluded that the stability of folded proteins is significantly ORCID Dor Ben-Amotz: 0000-0003-4683-5401 influenced by “water’s density and energy fluctuations”.138 However, the significance of this conclusion would be clarified Notes if such calculations were extended to separately quantify the The author declares no competing financial interest. influence of water structure on the solute−water and water−water (strictly compensating) energetic and entropic ■ ACKNOWLEDGMENTS contributions to protein-folding. Contributions to the cited publications from numerous Vibrational-MCR provides a means of experimentally graduate and undergraduate students, postdoctoral fellows, probing solute-induced changes in water structure. In dilute visiting scientists, and collaborators, as well as studies carried solutions, these structure changes pertain to the hydration- out by other authors, are gratefully acknowledged. This work shells of isolated solute molecules. The corresponding was supported by the National Science Foundation (CHE- hydration-shell structures have been found to be strongly 109746). temperature dependent,13,31,33 but the influence of such changes on aggregation and self-assembly remains to ■ REFERENCES determined. The same is true for influence of crowding on (1) Ball, P. Water is an active matrix of life for cell and molecular water-mediated and ion-mediated interactions, although the biology. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 13327.

10576 DOI: 10.1021/jacs.9b02742 J. Am. Chem. Soc. 2019, 141, 10569−10580 Journal of the American Chemical Society Perspective

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