Why Does Water Accelerate Organic Reactions under Heterogeneous

Article pubs.acs.org/JPCA

Why Does Water Accelerate Organic Reactions under Heterogeneous Condition? Arpan Manna and Anil Kumar* Physical and Materials Chemistry Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India S Supporting Information *

ABSTRACT: An exhaustive kinetic analysis has been carried out to offer the convincing evidence of the involvement of the oil−water interface in guiding “on water organic reaction” mechanism. We have tuned the interface to prove its indispensable efficacy to make on water reaction a unique type among water mediated organic reactions. Sensitive techniques have established the preferential solvation of polarizable ions at the water surface. The experimental methods have been developed to control the molecular structure of oil−water interface in situ. Temperature-dependent analyses have also been presented to understand the enthalpic and entropic modifications of the interfacial water molecules during a heterogeneous reaction. Both of our kinetic and thermodynamic outcomes have univocally established that the hydrogen-bonding ability of the surface water molecules plays a critical role in deciding the on water organic reaction mechanism. The results have important implications on understanding the role of small water molecules adjacent to the reactants during the reactions discussed in this investigation.

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Lewis acid catalysis13 of the solvent. The rate variations in the presence of salts have been discussed in terms of pro- and antihydrophobic agents.3,11b,14 Hydrophobic interactions have been observed to be the key force for both in water and on water conditions.15,16 Incidentally, the degree of rate acceleration varies between different reaction classes.1 This suggests that the interactions and orientation of the substrates with respect to water medium play a crucial role in determining the mechanism of these on water reactions. A much argued rate acceleration for multistep organic reactions like Ugi, Passerini, and ene with the apolar organic moieties in heterogeneous conditions has been explained underlining the ease of phase transfer during vigorous stirring, vortex formation, and ultrasonication techniques.15 On the other hand, the free OH groups at the oil−water interface16 as confirmed spectroscopically by Du et al.17 in the case of air− water interface help in stabilizing the organic reactants as well as the transition state through trans phase hydrogen bonding.16 Acevedo and Armacost emphasize the site-specific stabilization of the transition state as well as the destabilization of the reactants guiding the accessibility of the organic substrates to the water surface during molecular simulation study of Claisen rearrangements at on water condition.18 The on water nucleophilic substitution with the series of benzylic alcohols invoking carbocation intermediates indicates the acidic nature of the water surface.19 Thomas et al. have reported that water acted as a weak Brønsted acid to catalyze the heterogeneous reactions.20 Though they predicted the preferential stabilization

INTRODUCTION A recent fundamental discovery that the reaction time for a heterogeneous mixture of reactants and water is dramatically shorter than for homogeneous mixture in water is of great industrial importance.1 These heterogeneous types of organic reactions in the presence of water are further highlighted by Klijn and Engberts.2 This exciting observation is in comparison to that made in homogeneous mixtures of reactants in which it was noted that simple Diels−Alder reactions could be accelerated by many folds in water as compared to in conventional organic solvents.3 An equally significant contribution made by Grieco et al. underlined the importance of water as a solvent medium in organic synthesis.4 Since then, several experimental and theoretical studies have appeared in the literature describing the water-promoted organic reactions.5 One can design the same reaction under heterogeneous conditions in which water plays the role of medium only and not of solvent. These reactions are termed as “on water” reactions as recommended by Narayan et al.1 In terms of contributions made by Narayan et al., water as a solvent should be the sole medium for the reaction without the presence of any organic solvents, and the substrates used for the reactions should not be less than 0.1 M in concentration for the preparative purposes.6 Several reports describing the enhancement of the organic reactions at on water condition are available in the literature.7 Reviews are available covering many examples of water-promoted heterogeneous reactions in a systematic manner.8 The origin of forces responsible for spectacular rate enhancement of water-mediated homogeneous or “in water” organic reactions has been ascribed to several factors such as solvent polarity,9 hydrogen bonding,10 hydrophobic packing,11 enforced hydrophobic interaction,12 and © 2013 American Chemical Society

Received: January 10, 2013 Revised: February 28, 2013 Published: March 4, 2013 2446

dx.doi.org/10.1021/jp4002934 | J. Phys. Chem. A 2013, 117, 2446−2454

The Journal of Physical Chemistry A

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acquisition of the rate data, the relative peak area was calibrated with respect to the amount of product. Ten millimoles of aldehyde 4 and of ylide 5 each were suspended in 1 mL of water, and the mixture was subjected to vigorous stirring to avoid aggregation of ylide. The decrease in concentration of aldehyde with respect to time was observed by using UV visible spectrophotometer. From the decrease in the absorbance value with respect to the progress of the reaction, the second-order rate constant, k2, was determined in each case. Each experiment was carried out in triplicate with a standard error in k2 as ±6%. The reaction was also performed at temperatures from 25 to 45 °C using the single cell Peltier supplied with the spectrophotometer.

of the transition state through hydrogen bonding as one of the reasons of acceleration of Diels−Alder reactions, they were skeptical about the catalyzing power of the dangling OH groups at the oil−water interface. A recent study on the pH variation of the oil−water interface indicated that the promotion of organic reactions at on water condition could benefit from the protonated substrate, which is a result of preferential adsorption of OH ions at the interface.21 The authors have analyzed the deuterium isotope effect in terms of acid catalysis at the oil− water interface. The above developments, however, are not adequate in order to understand the factors responsible for the spectacular rate enhancement under heterogeneous conditions. The important barrier to study the role of water at the liquid− liquid interface is the continuous variation of the surface in the experimental time frame, which restricts the researchers to isolate the interfacial zone for their further investigations. Our report serves the purpose by designing experimental criteria to obtain a clear picture out of real reaction at heterogeneous conditions. In this work, we have attempted to investigate the interactions prevailing at the asymmetric environment at the organic-water juncture point acting as promoter of the reactions at heterogeneous conditions.

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RESULTS AND DISCUSSION The reaction of 1 with 2a (Scheme 1) was carried out at different stirring speeds of the magnetic stirrer keeping all other Scheme 1. Reaction of Cyclopentadiene (1) and Alkyl Acrylate (2)

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EXPERIMENTAL SECTION Materials. Cyclopentadiene 1 was freshly cracked from dicyclopentadiene prior to its use, while methyl acrylate 2a, ethyl acrylate 2b, and butyl acrylate 2c were distilled prior to their use. Benzaldehyde 4 was freshly distilled prior to its use. All commercially available salts KF, KCl, KBr, and KI were dried under vacuum for 6 h prior to their use in the reactions. All chemicals were procured from M/S Merck Chem. Extra Pure ammonia solution (30% v/v) was supplied by a commercial firm. Ylide 5 was freshly prepared in the laboratory.22 1H NMR spectrum of the product and the ylide were recorded in order to confirm their identities and to rule out the occurrence of any side reactions. Drop-Size Measurement. First, the size of a capillary was measured to correlate the pixel of Redlake High Speed Camera with 512 × 512 pixels in order to treat this as a reference for further measurements. The pictures were captured at a speed 230 frame per second at different rpm values. The snapshots were taken locating a particular bubble at a specific rpm from different angles, and radii were measured at different points. During the experiment, the maximum existence time of the bubble was taken not more than one second. The optical measurement was performed from different angles. The rootmean-square deviation of the entire radius obtained for each bubble from five different angles was calculated to include the deformation of the bubbles during experimental time of observation of 4 mS. For each rpm value of the stirrer, an average radius of five bubbles was treated as the radius of the bubble in question. Radius values of corresponding rpm values of the magnetic stirrer have been given in the Supporting Information. Kinetic Analysis. In a standard kinetic run, the reaction was initiated by adding 2a (1 M) to the reaction mixture of 1 (1 M) in 25 mL of water at 298.15 K. The temperature was controlled by a Julabo constant temperature bath with an accuracy of ±0.01 K. The reaction progress was monitored by GC (Varian CP-3800 gas chromatograph) by withdrawing 1 mL of reaction mixture after each interval of time followed by the extraction with ether. The k2 values were determined after measuring the relative peak area of the product with respect to time. Before

physical parameters the same. With the increase in the stirring speed, the size of the organic bubbles decreases steadily. As the solubility of the organic reactants in water is negligible, these organic bubbles have been assumed as homogeneous. Figure 1

Figure 1. A plot describing the change in interfacial area against the rpm value of the stirrer for the reaction between 1 with 2a; the connecting line is shown to guide the reader’s eye.

displays the change in the interfacial area with respect to the stirring speed. Introduction of the heterogeneity in terms of interface modifies the reaction in a manner that the activation energy is minimized even more than its homogeneous analogue. Figure 2 depicts the increment of the k2 values for the reaction between 1 and 2a with the stirring speed given in rpm keeping all other physical parameters unchanged. To ascertain the physical characteristics of the interface, we carried out the reaction in the presence of a minute amount of water to develop the clear and stable interface between the reactants 1 and 2a. We have performed the above reaction both with stirring and without stirring at 298.15 K. The k2 values 2447



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molecules with better diasteroslectivity than normal organic solvents.24b Here, the union of the reactants as the activated complex leads to product formation because of hydrophobic interactions by water.12b As we have discussed in the Introduction that enforced hydrophobic interaction seems to be present in promotion of both the mechanisms, our kinetic data with hexane solvent stress upon the absence of hydrophobicity of water in the said solvents because of the lack of the extensive hydrogen bonding network. We have performed the reactions of 1 with the reactants 2a, 2b, and 2c having varying hydrogen bonding capability in the decreasing order from 2a to 2c (Scheme 1). The temperature dependence of the rate constants of our reactions between 1 with 2a, 2b, and 2c at both on water and in water condition gives the results displayed in Table 1. A closer look at the data suggests that the hydrogen-bonding ability of the reactants with the neighboring water molecules of the droplets calls upon changes at the heterogeneous conditions of the reaction. As we vary the reactants from 2a to 2b to 2c, we are indirectly decreasing the hydrogen-bonding ability of the reactants; the comparative values make it obvious that the enthalpy values in the case of homogeneous reactions, that is, in water reactions, are not too sensitive to the hydrogenbonding competence of reactants. However, a cursory look on the enthalpy and entropy values of reactions in heterogeneous conditions ascertains the fact that as the potential of hydrogen bonding is decreased, the exothermic nature of the enthalpy is decreased. It implies that the bond formation is accompanied by exothermic change in the enthalpy and by the decrease in the entropy. This advocates that our results highlight the value of the change in enthalpies, that is, the energy is effectively used in bonding in due course of the reactions to modify the activation energy diagram in favor of positive catalysis by the interface. A recent finding by Kunieda et al. regarding the accumulation of aromatics at the oil−water interface supports our experimental observation of the formation of hydrogen bonding with the reactants and the transition state at the interface.24 They have explained the lowering of surface tension in the presence of aromatics with the introduction of weak hydrogen bonding between water at the interface and the aromatic molecules like benzene and toluene. To investigate the peculiarity in the interface in terms of its participation as catalyst, we designed our experiments in a manner to achieve control over the structural arrangements and availability of water molecules at the oil−water interface in situ. It is known to us that mutual polarization among water molecules is one of the main reasons for cooperative water− water hydrogen bonding, and it increases the strength of hydrogen bonding around 20%.25 The addition of any external reagent in the reaction medium that can tune this mutual polarization among water molecules will come out with the information of bonding at the interface. We have performed the experiments according to Scheme 2 at heterogeneous condition using water as a solvent medium.

Figure 2. A plot showing the variation of the k2 values vs rpm values for the reaction of 1 with 2a; the connecting line is shown to guide the reader’s eye.

obtained from these experiments are 1.21 × 10−5 M−1 s−1 and 2.86 × 10−7 M−1 s−1 with and without stirring, respectively. The data emphasize that the nature of the oil−water interface is microinterface, that is, an interface of which the physical appearance is not detectable unless vigorous stirring is carried out. A sharp increase in the k2 values (Figure 1) with respect to the area of the interface keeping all other physical parameters constant helps us to guide our further experimental designing to reveal the key factors relating to the interface in promotion of the reaction at heterogeneous conditions. The area of the bubbles has been calculated from the radius value obtained in each rpm value by A = πr2 where A = area and r = radius of the bubble. The total area during stirring at each rpm has been measured fixing the volume of the added reactants to water. An introduction of interface invokes asymmetry in a continuous dielectric field of water. The water−water hydrogen bonds possess 20 kJ/mol of energy, which is 10 times that of kT with kT being normal thermal strength at 298.15 K;23 k is the Boltzmann constant. We have accomplished the reaction of 1 with 2a (Scheme 1) in the presence of hexane as a substitute medium of water in heterogeneous condition. A heterogeneous phase has been created in this case by dissolving the reactants which cross the solubility limit of the reactants in hexane. The observed value of k2 turns out as 1.528 × 10−8 M−1 s−1, which is about 100 times slower than under on water condition. It establishes the fact that the presence of microinterface is an essential factor for the promotion of such heterogeneous reactions. The nature and bonding of interface also play a significant role here. The in water protocol seems largely dependent upon enforced hydrophobic interactions as proposed by Klijn and Engberts. Here, the enforced term is invoked as an organic reaction between apolar moieties enhances the hydrophobic interactions provided by water only. The reaction turns to enthalpy driven during hydrophobic interaction from entropy driven hydrophobic hydration of the apolar reactants in water. Our result has also been supported by the study of water promoted asymmetric synthesis of chiral

Table 1. Activation Parameters Derived from the Reaction between 1 with 2a, 2b, and 2c (Scheme 1) 1 + 2a #

−1 −1

1 + 2b #

−1

#

−1 −1

1 + 2c

type of reaction

Δ S (J mol K )

Δ H (k J mol )

Δ S (J mol K )

Δ H (k J mol )

Δ S (J mol K )

Δ#H (k J mol−1)

homogeneous heterogeneous

−75.65 −147.24

88.32 57.18

−72.16 −134.52

89.79 60.74

−66.37 −113.9

88.39 67.49

2448

#

−1

#

−1 −1



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Scheme 2. Wittig Reaction between Benzaldehyde 4 and Phosphonium Ylide 5 at 298.15 K in Heterogeneous Condition

The addition of salts having polarizability with the increasing order to the reaction medium may cause remarkable effects on the k2 values. Figure 3 shows the nonlinear decay in the k2 Figure 4. A plot depicting the change in the k2 vs the concentration of KI salt for the reaction between 4 and 5.

concentrations, the NH3 molecules simply bind with a small portion of water molecule at the interface through hydrogen bonding. As the ammonia molecule itself acts as a weak hydrogen bond donor to the water molecule, it simply occupies the free hydrogen bonding sites of water at the oil−water interface during the process.29 The illustration in Figure 5 gives a vivid description of the mechanism of adsorption. The process continues until saturation of the interface with ammonia molecules. Figure 3. A plot showing the variation of k2 vs polarizability for the reaction of 4 with 5 at 298.15 K.

values with respect to the polarizability of increasing order. Our observation of the change in the rate constants for the reaction in the presence of ions validates our understanding regarding ion specificity at the organic−water interface. This correlates well with the observation made by McFearin and Richmond that the hydrophobic organic molecules experience some hydrogen bonding through the water molecules present at the interface and that the presence of monovalent and divalent anions affects the nature of hydrogen bonding. This encouraged us to think over the molecular reasons that can explain the kinetic profiles of the heterogeneous reactions using water as a medium.26 Herein, the k2 values decrease with the increase in the polarizability of the ions from F− to I−, which can be explained as the more polarizable ions like Br− and I− reside at the reactant−water interface more preferably than F− and Cl− do. We have performed the same reaction in the presence of increasing concentrations of KI keeping all other parameters identical. Figure 4 shows that the k2 values for the reaction of 4 with 5 decrease with an increase in the concentration of I− in the reaction medium. Not only is the water surface enriched with the large polarizable anions but also its affinity for protons can resolve the molecular nature of the interface. H3O+ ions show higher propensity toward the surface for being a polarizable cation.27b Unfortunately, we cannot repeat the experiments given in our reaction schemes in the presence of acids as this affects the reactants also leading to side products. To avoid this situation, we have chosen to use polarizable ammonia−water mixtures in the reaction media in order to discern the effect of polarizable cations in the modification of the interface. Our selection of ammonia, a large polarizable ion, is motivated from atmospheric chemistry, which is a branch of chemistry that mainly deals with the sensitivity of the air−water interface toward the exposure of gas from the air.28 At very low

Figure 5. The diagram illustrates the capping of ammonia with the free OH groups.

Our experiment of the Wittig reaction (Scheme 2) in the presence of ammonia−water solutions of varying concentrations offers the kinetic data in Figure 6. As seen in Figure 6, a 10-fold decrease in the k2 values at the very low concentrations of ammonia is a consequence of the scarcity of hydrogen bond

Figure 6. A plot describing the variation of k2 with the concentration of ammonia in water in the reaction between 4 and 5. 2449



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donor sites of interfacial water molecules to the organic reactants as ammonium ions have preferably consumed the surface water molecules through hydrogen bonding. A meticulous observation of the graph confirms that the k2 values are insensitive to the higher concentrations of ammonia in the reaction medium. To obtain the alteration in the kind of hydrogen bonding, we introduced D2O as a cosolvent in our experiment, that is, on water Wittig reaction (Scheme 2). A thorough examination of these results exhibited in Figure 7 makes it obvious that there is

Table 2. Activation Parameters Derived for the Reaction of 4 and 5 in the Aqueous D2O Solutions of 1.0, 1.5, and 2.0 M concn of D2O (M)

Δ#H k J mol−1

Δ#S J mol−1 K−1

1.0 1.5 2.0

51.47 57.73 40.66

−147.65 −126.78 −179.76

hydration, which is a process of dissolution of hydrophobic molecules in water, thermodynamically it is associated with the large and negative value of Δ#S.12 It can be concluded that some of the degrees of freedom of the reactants and also of the transition state are restricted leading to a rise in entropy. However, the values of activation enthalpy lead us to conclude that from the intersection point the transition state of the Wittig reaction is stabilized through new bond formation. Alternatively, the exchange of hydrogen of ylide by deuterium at the higher concentration of D2O cannot be ruled out.30 On the basis of the neutron and X-ray diffraction studies, intramolecular hydrogen bonding in D2O can lead to OD···D bond that may be stronger at the transition state.31 We understand that temperature-dependent kinetic data do not lead to separate the thermal effect from those emanating out of the dangling OH groups. The exploitation of specific attributes of the polarizable salts, ammonia−water solution, and D2O during the study of the on water reactions can be validated from their contribution in altering the interfacial structure at the molecular level. Our commentary on the decrease in the rate constants with respect to the increment of the polarizability of anions of the potassium salt (Figure 3) supports the modern vibrational sum frequency spectroscopy (VSFS) and molecular dynamics (MD) studies of the arrangement of ions at the liquid−liquid interface. These modern practices, which incorporate the water−ion interactions as well as the molecular structure of the interface, revealed the picture that there was a propensity of ions toward the surface.32−34 In the line of Onsager theory that ions prefer to stay at the bulk rather than at the surface to avoid the increment of surface tension, modern experiments are available to remodel the interface in the complex manner.35 As the presence of ions at the interface increases the depth of it compared to their absence in water, the interface can be divided by two regions: surface and subsurface.34 The highly polarizable anions are accumulated at the surface followed by the higher decrease in their density at the subsurface region.27a,34b Thus, overall Gibbs surface excess possesses negative value in the macroscopic scale.27c From Figure 7, one can understand the surface-driven electrostatic interactions in a vivid manner. The actual system is quite complicated as compared to the one depicted in the picture, and the electrostatic interaction between ions and surrounding water is the complex infusion of size, polarity, and polarizability of the ions. Sun et al. have shown that van der Waals force plays a crucial role in determining the distribution of ions at the water surface.36 The decrease in the k2 values with increasing polarizability can be explained by describing the molecular picture of the ions inside bulk water. When a small polarizable charge is placed in the bulk, it will certainly induce electrostatic force toward surrounding water molecules. The dipoles of the water molecules in the solvation shell will orient themselves to nullify the electrostatic imbalance arising out of the presence of the ion in the bulk. As long as the polarizability and the size of the anion remain small, the resultant imbalance will be very

Figure 7. A diagram showing the water molecules around a small ion in bulk and a large polarizable ion at the interface.

a smooth decrease in k2 values with the rise of concentration of D2O up to 1.5 M. It, however, shows a sharp incline in the concentration in excess of 1.5 M of D2O. The clear intersection point in this graph is at ∼1.8 M corresponding to the value of k2 as 0.97 M−1 s−1. The decrease in the rate constants at the initial stage is also supported by the enhanced viscosity of solution upon the addition of D2O,11a which constrains the increment in the local concentrations of the reactants. However, the increment is surprising to us. To discern the reason for a sudden change in the k2 values at about 1.8 M, we carried out temperaturedependent kinetic studies in the concentration range of 1 to 2 M D2O that is near the inversion point of Figure 8. An examination into the activation energy data in Table 2 reveals the fact that at the molar concentration at which the transition occurs, the enthalpy of the system favors the reaction (less endothermic). Considering the concept of hydrophobic

Figure 8. A plot showing the variation in the k2 vs the concentration of D2O in the reaction of 4 with 5. 2450



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with increasing concentration of the ammonium cation (Figure 6) in the reaction medium can be interrelated with the phenomenon of adsorption of ammonium at the water surface. During adsorption of the gases, the exchanged gas modifies the thermodynamics of the surface by forming microemulsions and controls the further dynamics of the gas adsorption on water surface. Higher surface affinity of ammonia is because of high energy cost for water to solvate ammonia.42 Davidovits et al. showed that transport across the interface requires the displacement of the solvent molecules at the subsurface layer, which required a comparative mass accumulation of the ammonia molecule at the interface.43 After saturating the surface, the hydrogen atoms of the ammonia as well as the nitrogen atoms begin to form aggregates among themselves through hydrogen bonding. These ammonia molecules through aggregation up to a critical value (where the surface free energy creates a thermodynamic barrier to the growth of the nucleus initially) serve as nuclei for further clustering. High molecular density at the interfacial region indicates that the interfacial molecules are somehow interconnected and bound.44 It implies that the cluster can take various forms of arrangements at the interface of the oil−water. The recent sum frequency generation (SFG) study at the air/ water interface puts a spectroscopic justification on the above explanation.45 Consequently, the ammonia clusters form a barrier between the organic reactants and the water. Our kinetic data reveal that the reaction in the presence of higher concentrations of ammonia is equivalent to the reaction occurring under neat conditions as ammonia clusters hinder organic droplets to come in contact with water molecules. One may note here that the organic bubbles can have the assistance from hydrogen bonding imparted by ammonia molecules, which are present as aggregates in between organic and water layers, but the trend in the values of the k2 values for the Wittig reaction reveals that though ammonia molecules can stabilize the reactants as well as the transition state through hydrogen bonding, the other responsible factors essential for waterpromoted reactions cannot be covered by these ammonium ions present at the oil−water interface. This experimental finding has again confirmed our previous finding with hexane regarding the essential presence of water as well as its hydrophobic property. Our experiments help us to analyze the requirement of the interface and the role of water in the on water reactions. The recent observation of the assistance of the on water reaction by the adsorption of OH− at the oil−water interface through the reaction of the reactant and surface water molecule46 can be argued because of the high cost of energy to adsorption and the enhanced selectivity toward hydroxide ions.47 A very recent paper claimed that the origin of the negative charging at the interface is through a trace of fatty acids present in the oil.48 These fatty acids after reacting with water transfer to the interface to show the adsorption of hydroxide ions. It is important to recognize that though water molecules are strongly bonded to the neighboring water molecules through hydrogen bonding in the bulk, at the surface, they are weakly arranged because of unavailability of a reasonable number of neighboring counterparts. The size and the polarizability of ions are sufficient to displace the water molecules from the oil− water interface. We have justified the peculiarity of the oil− water interface in comparison to bulk through many experiments.

little, that is, tends to zero. If the polarizability of the solvated anion rises, the surrounding water molecules will induce a large amount of dipole moment in the solvated anion. Therefore, large polarizable anions try to move toward the interface in order to get rid of the above unfavorable electrostatic destabilization caused by dipole-induced dipole moment.27c,37 The presence of ions at the interface leads to the effective hydrogen bonding at the subsurface layer of the water and minimizes the contact of the ions with neighboring water molecules. Consequently, the sufficient stabilization of anions overshadows the ion−water electrostatic interactions. The displacement of the water molecules from the interface by the presence of anions results in a decrease in the availability of the water molecules at the oil−water interface.30 This in turn imposes a serious consequence to the on water reactions as the reaction will not be facilitated by hydrophobic hydration as well as hydrogen bonding for lowering the activation energy of the reaction. A change in the VSFS spectra at the air−water interface38 as well as at the CCl4−water interface39 in the presence of several polarizable ions justifies the prediction. Here, a sharp decrease in the k2 values (Figure 4) with the salt concentration may originate from the fact that KI is a salting-in agent.40 One can, however, argue that upon addition of an increasing amount of KI in the system, the hydrophobicity of the system decreases.11b,14d A time-honored analysis of water structure-making or structure-breaking because of the salt effect induces us to examine whether our investigation can commonly be categorized by the salt effect rather than by the surface specificity of the polarizable ions in their aqueous solutions. The hydrophobicity plays a decisive role in the water-promoted reactions along with the role of the hydrogen-bonding ability. To separate out the effect of hydrophobicity from hydrogen bonding in the case of interfacial reactions, we repeated the Wittig reaction (Scheme 2) in the presence of the increasing amount of the KCl, a salting-out agent.40 KCl is a prohydrophobic salt and, hence, enhances the hydrophobicity. Figure 9 reveals a clear decrease in the k2 values with the

Figure 9. A plot showing the variation in values of k2 values with addition of KCl salt for the reaction of 4 with 5.

increase in concentration of KCl salt in the reaction media. Here, if only the salt effect had played the guiding role to modify the oil−water interface structure, then introduction of KCl salt could lead to the increase in the k2 values instead of to their decrease. Photodetachment spectroscopy has recently revealed that with increasing concentration, I− ions accumulate at the surface in an increasing order.41 Our results shed light on the molecular nature of the oil−water interface in the presence of salts. The outcomes concerning the drop in the k2 values 2451



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Chem. Rev. 2005, 105, 3095−3165. (b) Leach, A. G.; Houk, K. N.; Reymond, J.-L. Theoretical Investigation of the Origins of Catalysis of a Retro-Diels-Alder Reaction by Antibody 10F11. J. Org. Chem. 2004, 69, 3683−3692. (c) Wei, C. M.; Li, C. J. A Highly Efficient ThreeComponent Coupling of Aldehyde, Alkyne, and Amines via C−H Activation Catalyzed by Gold in Water. J. Am. Chem. Soc. 2003, 125, 9584−9585. (d) Lindstrom, U. M. Stereoselective Organic Reactions in Water. Chem. Rev. 2002, 102, 2751−2772. (e) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. Rhodium-Catalyzed Hydroarylation of Alkynes with Arylboronic Acids: 1,4-Shift of Rhodium from 2-Aryl1-alkenylrhodium to 2-Alkenylarylrhodium Intermediate. J. Am. Chem. Soc. 2001, 123, 9918−9919. (f) Nagayama, S.; Kobayashi, S. A Novel Chiral Lead(II) Catalyst for Enantioselective Aldol Reactions in Aqueous Media. J. Am. Chem. Soc. 2000, 122, 11531−11532. (g) Pindur, U.; Lutz, G.; Otto, C. Acceleration and Selectivity Enhancement of Diels-Alder Reactions by Special and Catalytic Methods. Chem. Rev. 1993, 93, 741−761. (h) Wijnen, J. W.; Engberts, J. B. F. N. Retro-Diels-Alder Reaction in Aqueous Solution: Toward a Better Understanding of Organic Reactivity in Water. J. Org. Chem. 1997, 62, 2039−2044. (i) Lubineau, A.; Auge, J.; Queneau, Y. WaterPromoted Organic Reactions. Synthesis 1994, 8, 741−760. (j) Muller, N. Search for a Realistic View of Hydrophobic Effects. Acc. Chem. Res. 1990, 23, 23−28. (k) Breslow, R.; Guo, T. Diels-Alder Reactions in Nonaqueous Polar Solvents. Kinetic Effects of Chaotropic and Antichaotropic Agents and of β-Cyclodextrin. J. Am. Chem. Soc. 1988, 110, 5613−5617. (6) Lindstrom, M. U. Organic Reactions in Water; Blackwell Publishing Ltd.: Oxford, U.K., 2007; Chapter 11. (7) For example, see (a) Shapiro, N.; Vigalok, A. Highly Efficient Organic Reactions “on Water”, “in Water”, and Both. Angew. Chem., Int. Ed. 2008, 47, 2849−2852. (b) Hayashi, Y. In Water or in the Presence of Water? Angew. Chem., Int. Ed. 2006, 45, 8103−8104. (c) Butler, R. N.; Coyne, A. G.; Moloney, E. M. Organic Synthesis in Water: 1,3-Dipolar Cycloaddition Reactions at Ambient Temperature with Aqueous Suspensions of Solid Reactants. Tetrahedron Lett. 2007, 48, 3501−3503. (8) (a) Simon, M. O.; Li, C. J. Green Chemistry Oriented Organic Synthesis in Water. Chem. Soc. Rev. 2012, 41, 1415−1427. (b) Butler, R. N.; Coyne, A. G. Water: Nature’s Reaction EnforcerComparative Effects for Organic Synthesis “In-Water” and “On-Water”. Chem. Rev. 2010, 110, 6302−6337. (c) Chanda, A.; Fokin, V. V. Organic Synthesis “On Water”. Chem. Rev. 2009, 109, 725−748. (9) (a) Jenner, G.; Ben Salem, R. Kinetic Effects in Water and Ethylene Glycol. Application to High Pressure Organic Synthesis. New J. Chem. 2000, 24, 203−207. (b) Cativiela, C.; Garcia, J. I.; Gil, J.; Martinez, R. M.; Mayoral, J. A.; Salvatella, L.; Urieta, J. S.; Mainar, A. M.; Abraham, M. H. Solvent effects on Diels-Alder reactions. The Use of Aqueousmixtures of Fluorinated Alcohols and the Study of Reactions of Acrylonitrile. J. Chem. Soc., Perkin Trans 2 1997, 653− 660. (c) Richardt, C. Solvent Effects in Organic Chemistry; Verlag Chemie: Weinheim, Germany, 1979; Chapter 2. (10) (a) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. Rate Acceleration of the Baylis−Hillman Reaction in Polar Solvents (Water and Formamide). Dominant Role of Hydrogen Bonding, Not Hydrophobic Effects, Is Implicated. J. Org. Chem. 2002, 67, 510− 514. (b) Van der Wel, G. K.; Wijnen, J. W.; Engberts, J. B. F. N. Solvent Effects on a Diels−Alder Reaction Involving a Cationic Diene: Consequences of the Absence of Hydrogen-Bond Interactions for Accelerations in Aqueous Media. J. Org. Chem. 1996, 61, 9001−9005. (c) Blake, J. F.; Lim, D.; Jorgensen, W. L. Enhanced Hydrogen Bonding of Water to Diels-Alder Transition States. Ab Initio Evidence. J. Org. Chem. 1994, 59, 803−805. (d) Blake, J. F.; Jorgensen, W. L. Solvent Effects on a Diels-Alder Reaction from Computer Simulations. J. Am. Chem. Soc. 1991, 113, 7430−7432. (11) (a) Itami, K.; Nokami, T.; Yoshida, J.-I. 2-Pyridyldimethylsilyl as a Removable Hydrophilic Group in Aqueous Diels−Alder Reactions. Angew. Chem., Int. Ed. 2001, 40, 1074−1076. (b) Jenner, G. Kinetic Effect of Pressure on Michael and Diels−Alder Reactions in Aqueous Solutions. J. Phys. Org. Chem. 1999, 12, 619−625. (c) Meijer, A.; Otto,

CONCLUSIONS Accomplishment of on water reaction and further scaling up of the product follow effortless pathways. The understanding of the mechanistic details demands exciting ways to solve the structural details at the liquid−liquid interface. The main focus of the present report was to delineate the arrangement of water molecules as well as their participation in the on water reactions as investigated in this work. Comparing the results and subsequent discussions, we arrive at the following conclusions. First, the presence of interface is essential criteria for the on water reactions. Second, the nature of the interface should be figured out in a way to maximize the contact between the reactant and the water. At last, the most crucial conclusion of our investigations is that the ease of the hydrogen bonding with the reactants and the transition state at the interface from the water molecules serve as vital requirements along with hydrophobicity and cohesive energy density offered by small water molecules. It is hoped that this investigation will enhance our understanding about other on water organic reactions and will help us in promoting water as the greener solvent and in designing a new green solvent possessing the structural features of water and large reaction window. This study, it is hoped, will lead to studies of complex liquid−liquid interfaces and their impact on organic reactions.

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ASSOCIATED CONTENT

S Supporting Information *

Protocols of in water and on water reactions, GC analysis, 1H NMR spectra, and kinetic data.This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +912025902278; E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors express their gratitude to all three anonymous reviewers for their fruitful comments and suggestions that led to the improvement of this manuscript. A.M. thanks CSIR, New Delhi, for awarding him a Junior Research Fellowship, while A.K. thanks DST, New Delhi, for awarding him a JC Bose National Fellowship (SR/S2/JCB-26/2009).

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REFERENCES

(1) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. “On Water”: Unique Reactivity of Organic Compounds in Aqueous Suspension. Angew. Chem., Int. Ed. 2005, 44, 3275−3279. (2) Klijn, E.; Engberts, J. B. F. N. Organic Chemistry: Fast Reactions. ‘On Water’. Nature 2005, 435, 746−747. (3) Rideout, D. C.; Breslow, R. Hydrophobic Acceleration of DielsAlder Reactions. J. Am. Chem. Soc. 1980, 102, 7816−7817. (4) (a) Grieco, P. A.; Ferrino, S.; Vidari, G. Total Synthesis Of DlQuassin. J. Am. Chem. Soc. 1980, 102, 7586−7587. (b) Vidari, G.; Ferrino, S.; Grieco, P. A. Quassinoids: Total Synthesis Of Dl-Quassin . J. Am. Chem. Soc. 1984, 106, 3539−3548. (c) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic & Professional: London, 1998; Chapter 3. (5) For example, see (a) Li, C. J. Organic Reactions in Aqueous Media with a Focus on C-C Bond Formations: A Decade Update. 2452



Article

Alcohols. Angew. Chem., Int. Ed. 2009, 48, 1313−1316. (b) Cozzi, P. G.; Zoli, L. A Rational Approach towards the Nucleophilic Substitutions of Alcohols “on Water”. Angew. Chem., Int. Ed. 2008, 47, 4162−4166. (20) Thomas, L. L.; Tirado-Rives, J.; Jorgensen, W. L. Quantum Mechanical/Molecular Mechanical Modeling Finds Diels−Alder Reactions Are Accelerated Less on the Surface of Water Than in Water. J. Am. Chem. Soc. 2010, 132, 3097−3104. (21) Beattie, J. K.; McErlean, C. S. P.; Phippen, C. B. W. The Mechanism of On-Water Catalysis. Chem.Eur. J. 2010, 16, 8972− 8974. (22) (a) Tiwari, S.; Kumar, A. Unusual Temperature Dependence of Salt Effects for “On Water” Wittig Reaction: Hydrophobicity at the Interface. Chem. Commun. 2008, 4445−4447. (b) Weleski, E. T.; Silver, J. L.; Jansson, M. D.; Burmeister, J. L. Palladium(II), Platinum(II) and Mercury(II) Complexes of Ambidentate Phosphonium, Arsonium, Sulfonium and Pyridinium Ylides. J. Organomet. Chem. 1975, 102, 365−385. (23) Water: A Comprehensive Treatise; Franks, F., Ed.; Plenium Press: New York, 1973; Vol. 1, Chapter 3. (24) (a) Kunieda, M.; Nakaoka, K.; Liang, Y.; Marinda, C. R.; Ueda, Akira; Takahasi, S.; Okabe, H.; Matsuoka, T. Self-Accumulation of Aromatics at the Oil−Water Interface through Weak Hydrogen Bonding. J. Am. Chem. Soc. 2010, 132, 18281−18286. (b) Lubineau, A.; Bienayme, H.; Queneau, Y.; Scherrmann, M. C. Aqueous Cycloadditions using Glyco-Organic Substrates - Thermodynamics of the Reaction. New J. Chem. 1994, 18, 279−285. (25) Jeffry, G. A.; Sanger, W. Hydrogen Bonding in Biological Structures; Springer: Berlin, 1991; Part IV. (26) McFearin, C. L.; Richmond, G. L. The Role of Interfacial Molecular Structure in the Adsorption of Ions at the Liquid−Liquid Interface. J. Phys. Chem. C 2009, 113, 21162−21168. (27) (a) Santos, A. P. D.; Levin, Y. Ions at the Water−Oil Interface: Interfacial Tension of Electrolyte Solutions. Langmuir 2012, 28, 1304− 1308. (b) Chang, T. M.; Dang, L. X. Recent Advances in Molecular Simulations of Ion Solvation at Liquid Interfaces. Chem. Rev. 2006, 106, 1305−1322. (c) Vrbkaa, L.; Muchaa, M.; Minofara, B.; Jungwirth, P.; Brownb, E. C.; Tobiasb, D. J. Propensity of soft ions for the air/ water interface. Curr. Opin. Colloid Interface Sci. 2004, 9, 67−73. (28) Donaldson, D. J. Adsorption of Atmospheric Gases at the Air− Water Interface. I. NH3. J. Phys. Chem. A 1999, 103, 62−70. (29) Simonelli, D.; Baldelli, S.; Shultz, M. J. Ammonia-Water Complexes on the Surface of Aqueous Solutions Observed with Sum Frequency Generation. Chem. Phys. Lett. 1998, 298, 400−404. (30) El-Batta, A.; Jiang, C.; Zhao, W.; Anness, R.; Cooksy, A. L.; Bergdahl, M. Wittig Reactions in Water Media Employing Stabilized Ylides with Aldehydes. Synthesis of α,β-Unsaturated Esters from Mixing Aldehydes, α-Bromoesters, and Ph3P in Aqueous NaHCO3. J. Org. Chem. 2007, 72, 5244−5259. (31) Soper, A. K.; Benmore, C. J. Quantum Differences between Heavy and Light Water. Phys. Rev. Lett. 2008, 101, 65502/1−65502/4. (32) (a) Scatena, L. F.; Brown, M. G.; Richmond, G. L. Water at Hydrophobic Surfaces: Weak Hydrogen Bonding and Strong Orientation Effects. Science 2001, 292, 908−912. (b) Du, Q.; Freysz, E.; Shen, Y. R. Surface Vibrational Spectroscopic Studies of Hydrogen Bonding and Hydrophobicity. Science 1994, 264, 826−828. (c) Perera, L.; Berkowitz, M. L. Many-Body Effects in Molecular Dynamics Simulations of Na+(H2O)n and Cl−(H2O)n Clusters. J. Chem. Phys. 1991, 95, 1954−1963. (33) Dang, L. X.; Smith, D. E. Molecular Dynamics Simulations of Aqueous Ionic Clusters Using Polarizable Water. J. Chem. Phys. 1993, 99, 6950−6956. (34) (a) Walker, D. S.; Richmond, G. L. Depth Profiling of Water Molecules at the Liquid−Liquid Interface Using a Combined Surface Vibrational Spectroscopy and Molecular Dynamics Approach. J. Am. Chem. Soc. 2007, 129, 9446−9451. (b) Jungrith, P. D.; Tobias, J. Molecular Structure of Salt Solutions: A New View of the Interface with Implications for Heterogeneous Atmospheric Chemistry. J. Phys. Chem. B 2001, 105, 10468−10472.

S.; Engberts, J. B. F. N. Effects of the Hydrophobicity of the Reactants on Diels−Alder Reactions in Water. J. Org. Chem. 1998, 63, 8989− 8994. (d) Breslow, R.; Conners, R. V. Quantitative Antihydrophobic Effects as Probes for Transition State Structures. 1. Benzoin Condensation and Displacement Reactions. J. Am. Chem. Soc. 1995, 117, 6601−6602. (e) Blokzijl, W.; Engberts, J. B. F. N. Hydrophobic Effects. Opinions and Facts. Angew. Chem., Int. Ed. Engl. 1993, 32, 1545−1579. (f) Breslow, R. Hydrophobic Effects on Simple Organic Reactions in Water. Acc. Chem. Res. 1991, 24, 159−164. (g) Lubineau, A.; Auge, J.; Lubin, N. Aqueous Cycloaddition using Glyco-Organic Substrates. Facial Stereoselectivity In Diels−Alder Reactions of a Chiral Diene Derived from D-Glyceraldehyde. J. Chem. Soc., Perkin Trans. 1 1990, 3011. (h) Brandes, E.; Grieco, P. A.; Garner, P.; Garner, P. Diastereoselection in an Aqueous Diels-Alder Reaction: A Formal Total Synthesis of the Inhoffen-Lythgoe Diol. J. Chem. Soc., Chem. Commun. 1988, 500. (12) (a) Engberts, J. B. F. N. Diels-Alder Reactions in Water: Enforced Hydrophobic Interaction and Hydrogen Bonding. Pure Appl. Chem. 1995, 67, 823−828. (b) Blokzijl, W.; Engberts, J. B. F. N.; Blandamer, M. J. Diels-Alder Reactions in Aqueous Solutions. Enforced Hydrophobic Interactions between Diene and Dienophile. J. Am. Chem. Soc. 1991, 113, 4241−4246. (c) Blokzijl, W.; Engberts, J. B. F. N.; Blandamer, M. J. Quantitative Analysis Of Solvent Effects in Highly Aqueous Media. Application of the SWAG Procedures and A Critical Appraisal of the Additivity Principle. J. Am. Chem. Soc. 1990, 112, 1197−1201. (13) (a) Mubofu, E. B.; Engberts, J. B. F. N. Specific Acid Catalysis and Lewis Acid Catalysis of Diels−Alder Reactions in Aqueous Media. J. Phys. Org. Chem. 2004, 17, 180−186. (b) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Recent Advances in Lewis Acid Catalyzed Diels−Alder Reactions in Aqueous Media. Eur. J. Org. Chem. 2001, 439. (c) Kobayashi, S.; Nagayama, S.; Busujima, T. Lewis Acid Catalysts Stable in Water. Correlation between Catalytic Activity in Water and Hydrolysis Constants and Exchange Rate Constants for Substitution of Inner-Sphere Water Ligands. J. Am. Chem. Soc. 1998, 120, 8287−8288. (d) Garcia, J. I.; Martinez-Merino, V.; Mayoral, J. A.; Salvatella, L. Density Functional Theory Study of a Lewis Acid Catalyzed Diels−Alder Reaction. The Butadiene + Acrolein Paradigm. J. Am. Chem. Soc. 1998, 120, 2415−2420. (e) Otto, S.; Bertoncin, F.; Engberts, J. B. F. N. Lewis Acid Catalysis of a Diels−Alder Reaction in Water. J. Am. Chem. Soc. 1996, 118, 7702−7707. (f) Loh, T.-P.; Pei, J.; Lin, M. Indium Trichloride (InCl3) Catalysed Diels−Alder Reaction in Water. Chem. Commun. 1996, 2315−2316. (14) (a) Beattie, J. K.; Djerdjev, A. M. The Pristine Oil/Water Interface: Surfactant-Free Hydroxide-Charged Emulsions. Angew. Chem., Int. Ed. 2004, 43, 3568−3571. (b) Kumar, A. Salt Effects on Diels−Alder Reaction Kinetics. Chem. Rev. 2001, 101, 1. (c) Garner, P. P. In Organic Synthesis in Water. Diels−Alder Reactions in Aqueous Media; Grieco, P. A., Ed.; Blackie: Glassgow, U.K., 1998; Chapter 1. (d) Breslow, R.; Rizzo, C. J. Chaotropic Salt Effects in a Hydrophobically Accelerated Diels-Alder Reaction. J. Am. Chem. Soc. 1991, 113, 4340−4341. (15) (a) Pirrung, M. C.; Sarma, K. D.; Wang, J. Hydrophobicity and Mixing Effects on Select Heterogeneous, Water-Accelerated Synthetic Reactions. J. Org. Chem. 2008, 73, 8723−8744. (b) Pirrung, M. C.; Sarma, K. D. Aqueous Medium Effects on Multi-component Reactions. Tetrahedron 2005, 61, 11456−11472. (c) Pirrung, M. C.; Sarma, K. D. Multicomponent Reactions Are Accelerated in Water. J. Am. Chem. Soc. 2004, 126, 444−445. (16) Jung, Y.; Marcus, R. A. On the Theory of Organic Catalysis “on Water”. J. Am. Chem. Soc. 2007, 129, 5492−5502. (17) Du, Q.; Superfine, R.; Freysz, E.; Shen, Y. R. Vibrational Spectroscopy of Water at the Vapor/Water Interface. Phys. Rev. Lett. 1993, 70, 2313−2316. (18) Acevedo, O.; Armacost, K. Claisen Rearrangements: Insight into Solvent Effects and “on Water” Reactivity from QM/MM Simulations. J. Am. Chem. Soc. 2010, 132, 1966−1975. (19) (a) Cozzi, P. G.; Benfatti, F.; Zoli, L. Organocatalytic Asymmetric Alkylation of Aldehydes by SN1-Type Reaction of 2453



Article

(35) Onsager, L.; Samaras, N. N. T. The Surface Tension of DebyeHückel Electrolytes. J. Chem. Phys. 1934, 2, 528−536. (36) Sun, L.; Li, X.; Hede, T.; Tu, Y.; Leck, C.; Ågren, H. Molecular Dynamics Simulations of the Surface Tension and Structure of Salt Solutions and Clusters. J. Phys. Chem. B 2012, 116, 3198−3204. (37) Yoo, S.; Lei, Y. A.; Zengb, X. C. Effect of Polarizability of Halide Anions on the Ionic Solvation in Water Clusters. J. Chem. Phys. 2003, 119, 6083−6091. (38) Liu, D.; Ma, G.; Lavering, L. M.; Allen, H. C. Vibrational Spectroscopy of Aqueous Sodium Halide Solutions and Air−Liquid Interfaces: Observation of Increased Interfacial Depth. J. Phys. Chem. B 2004, 108, 2252−2260. (39) Raymond, E. A.; Richmond, G. L. Probing the Molecular Structure and Bonding of the Surface of Aqueous Salt Solutions. J. Phys. Chem. B 2004, 108, 5051−5059. (40) Deshpande, S. S.; Phalgune, U. D.; Kumar, A. Salt Effect on the Endo/Exo Ratio of the Reaction of Cyclopentadiene with Methyl Methacrylate. Tetrahedron 2002, 58, 8759−8762. (41) Hiranuma, Y.; Kaniwa, K.; Shoji, M.; Mafune, F. Solvation Structures of Iodide on and below a Surface of Aqueous Solution Studied by Photodetachment Spectroscopy. J. Phys. Chem. A 2011, 115, 8493−8497. (42) Carignano, M. A.; Jacob, M. M.; Avila, E. E. On the Uptake of Ammonia by the Water/Vapor Interface. J. Phys. Chem. A 2008, 112, 3676−3679. (43) Davidovits, P.; Hu, J. H.; Worsnop, D. R.; Zahniser, M. S.; Kolb, C. E. Entry of Gas Molecules into Liquids. Faraday Discuss. 1995, 100, 65−81. (44) Nathanson, G. M.; Davidovits, P.; Wornop, D. R.; Kolb, C. E. Dynamics and Kinetics at the Gas−Liquid Interface. J. Phys. Chem. 1996, 100, 13007−13020. (45) Shultz, M. J.; Baldelli, S.; Schnitzer, C.; Simonelli, D. Aqueous Solution/Air Interfaces Probed with Sum Frequency Generation Spectroscopy. J. Phys. Chem. B 2002, 106, 5313−5324. (46) Beattie, J. K.; Djerdjev, A. M. The Pristine Oil/Water Interface: Surfactant-Free Hydroxide-Charged Emulsions. Angew. Chem., Int. Ed. 2004, 43, 3568−3571. (47) (a) Creux, P.; Lachaise, J.; Graciaa, A.; Beattie, J. K.; Djerdjev, A. M. Strong Specific Hydroxide Ion Binding at the Pristine Oil/Water and Air/Water Interfaces. J. Phys. Chem. B 2009, 113, 14146−14150. (b) Marinova, K. G.; Alargova, R. G.; Denkov, N. D.; Velev, O. D.; Petsev, D. N.; Ivanov, I. B.; Borwankar, R. P. Charging of Oil−Water Interfaces Due to Spontaneous Adsorption of Hydroxyl Ions. Langmuir 1996, 12, 2045−2051. (48) Roger, K.; Cabane, B. Why Are Hydrophobic/Water Interfaces Negatively Charged? Angew. Chem., Int. Ed. 2012, 51, 5625−5628.

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