Superacid Chemistry on Mildly Acidic Water † ‡ † † Shinichi Enami, Logan A

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Superacid Chemistry on Mildly Acidic Water † ‡ † † Shinichi Enami, Logan A. Stewart, Michael R. Hoffmann, and Agustín J. Colussi*, † W. M. Keck Laboratories, California Institute of Technology, Pasadena, California 91125, United States, and ‡ Department of Physics, University of California, Santa Barbara, California 93106, United States

ABSTRACT The mechanism of proton transfer across water-hydrophobic media boundaries is investigated in experiments in which the protonation of gaseous n-hexanoic acid (PCOOH) upon collision with liquid water microjets is monitored by online electrospray mass spectrometry as a function of pH. Although PCOOH(aq) is þ ( K þ - ) ( ) ( ) a very weak base p BH < 3 , PCOOH g is converted to PC OH 2 on pH < 4 water via a process that ostensibly retains some of the exoergicity of its gas-phase þ þ ( ) þ þ ΔG - -1 counterpart, PCOOH H3O =PC OH 2 H2O, < 22 kcal mol . The large ( ) þ ( ) þ kinetic isotope effects observed on H2O/D2O microjets, PC OH 2 /PC OH OD = ( ) þ ( ) þ 88 and PC OH OD /PC OD 2 = 156 at pD = 2, and their inverse dependences on pH indicate that PCOOH(g) hydronation on water (1) involves tunneling, (2) is faster than H-isotope exchange, and (3) is progressively confined to the outermost layers as water becomes more acidic. Proton transfers across steep water density gradients appear to be promoted by both dynamic and thermodynamic factors. SECTION Atmospheric, Environmental and Green Chemistry

( ) ( ) ( ) arious classes of chemical reactions have been found gas-phase basicities GB larger than H2O, GB B >GB H2O = -1 26 þ( ) to proceed faster and/or along different pathways at 158 kcal mol , and are readily protonated by H3O g ,as - water boundaries with hydrophobic phases.1 4 These evinced by the versatility of proton-transfer reaction mass V 27 þ ( ) phenomena have been tentatively ascribed to the peculiar spectrometry. The larger stabilities of H2O n 3 H3O versus 5-9 ( ) þ 28 structure oracidity of interfacial water. Herein, we advance H2O n 3 BH clusters, however, render the free energies of the notion that they are due both to the onset of favorable reactions that generate, annihilate, or interconvert charged thermochemistry and to the unique dynamics of proton species at water's surfaces (such as reaction R3) sensitive func- transfer under steep water density gradients. We point out that tions of n or, equivalently, of water density, Fw,particularlyabout F ≈ 29,30 these two conditions should generally arise during catalytic w 0. The empirical eq E1 encodes such functionality - events within enzyme active sites.10 19 ð Þþ þð Þ f þð Þþ ð ÞðÞ In the laboratory, Bronsted€ acidity scales are based on proton B s H3O s BH s H2O s R3 activity relative to a realizable standard state, or the posi- ΔG ðF Þ¼ΔG þðΔG - ΔG ÞF R < R < ð Þ tion of equilibria among conjugated acid/base pairs. Uniform 3 w 1 2 1 w 0 1 E1 proton activity/chemical potential across phases in thermo- Δ ( The exoergicity of gas-phase proton transfers, G1 = dynamic equilibrium ensures that local acidity defined, e.g., ( ) - ( ) as the pH of bulk water relative to a local standard state) GB H2O GB B < 0, is therefore expected to be exquisitely is a global acidity, even at water boundaries of widths com- tunable and eventually reversed with great economy of mensurate with the range of intermolecular forces.20,21 The motion within interfacial layers. Our report underscores the importance of this phenomenon. acidity of interfacial water is therefore identical to the acidity ( ) of bulk water (in the same standard state). Alternatively, A is In a recent study, trimethylamine, Me3N g , a strong base ( þ ) ( ( € ) both in bulk water pKBH =9.8 and in the gas phase GB = said to be a stronger Bronsted acid than B in any given -1) þ( ) medium if protons would bind preferentially to B. Because 227 kcal mol , could be captured as Me3NH s on water þ only at pH < 4 (rather than at pH < pKBHþ) in a process hydronium, H3O , can protonate most organic compounds þ( ) in the gas phase (reaction R1)22,23 but only relatively strong clearly controlled by the unavailability of interfacial H3O s bases in bulk water (reaction R2)24,25 in the pH>4 range rather than by unfavorable thermochemistry.5 It must be emphasized that such finding strictly þ þ þ BðgÞþH3O ðgÞ f BH ðgÞþH2OðgÞðR1Þ implies that H3O actually emerges to the surface of pH < 4 ( ) water, where it can protonate impinging Me3N g molecules þ þ ( BðaqÞþH3O ðaqÞ f BH ðaqÞþH2OðlÞðR2Þ during collision times not that the surface of 4 < pH < 7 it is apparent that the extent of protonation of Bronsted€ acids and bases on water's surface is determined not only by Received Date: October 12, 2010 (global) acidity but, critically, by their hydration status Accepted Date: December 1, 2010 therein. It is a remarkable fact that most nonalkanes have Published on Web Date: December 03, 2010

r 2010 American Chemical Society 3488 DOI: 10.1021/jz101402y |J. Phys. Chem. Lett. 2010, 1, 3488–3493 pubs.acs.org/JPCL

Scheme 1. Creation of a Microjeta in the Spraying Chamber of an Electrospray Mass Spectrometer by Injecting Acidified Water through an Electrically Grounded Nebulizer

a The microjet is briefly exposed to hexanoic acid vapors before it is broken up (at ∼10 μs) into charged microdroplets by the fast nebulizer gas. Upon subsequent solvent evaporation, ions in excess are ultimately ejected from the microdroplets via field desorption and detected by mass spectrometry within 1 ms. water is necessarily “basic”). On the basis of the preceding proportional to ion concentrations (up to a few mM) in the þ( ) 5,34 considerations, herein, we explore the possibility that H3O s interfacial layers of the microjets prior to their breakup. ( ) could protonate bases weaker than Me3N g , that is, whether See Experimental Methods and Figure S1 in the Supporting þ( ) þ( ) H3O s is a stronger proton donor than H3O aq of the Information, SI, for further details. The present study focuses ( ) þ ( ) same nominal acidity. In other words, we inquire whether on the evolution of PC OH 2 m/z =117 ESI signals as the thermochemistry of reaction R3 approaches that of functions of pH and solvent deuteration. ( ) þ reaction R1 or R2 on water's surface. Figure 1 shows the PC OH 2 ESI mass spectral m/z =117 ( ) ( ) We chose hexanoic acid, PCOOH, GB PCOOH = signal intensities, I11 7 , detected on 1 aqueous microjets -1 26 31 187 kcal mol >GB(H2O), pKBHþ < -3, as a suitable exposed to 77 ppbv PCOOH(g) and (2) microjets containing probe in experiments where reactive events on the surface 1mMPCOOH(aq), as functions of the pH of the bulk liquid. If ( ) ( ) ( ) of aqueous microjets exposed to PCOOH g /N2 g mixtures all PCOOH g collisions with the surface of microjets yielded þ for ∼10 μs are monitored by online electrospray ionization PC(OH)2 , that is, its uptake coefficient were γ ≈ 1, we esti- ( ) μ -1 11 ( ) þ( ) -2 mass spectrometry ESI-MS . A flow of 50 L min of water mate that <1.5 10 PC OH 2 s cm would be gener- (whose pH had been adjusted using concentrated HCl) was ated upon exposure to 77 ppbv PCOOH(g) for 10 μs.5 As - injected as a liquid microjet via an electrically grounded a reference, a 1 mM interfacial layer that is δ=1 10 7 cm - pneumatic nozzle (bore diameter: 100 μm) into the spraying deep contains 6 1010 PCOOH(aq) cm 2. It is apparent chamber of an ESI mass spectrometer held at 1 atm and that the reactive uptake of PCOOH(g) via protonation ap- ( ) ( ) ( ) 293 K Scheme 1 . The fast nebulizer gas N2 soon tore up proaches 100% efficiency, whereas predissolved PCOOH aq the outer layers of the microjet into microdroplets carrying (pKBHþ < -3) is minimally protonated at pH > 1. We infer 32 ( ) ( ) þ( ) ion excesses of either sign. Excess ions were eventually that PCOOH g is directly captured as PC OH 2 s on the þ( ) field-ejected to the gas phase from evaporating micro- surface of pH < 4 water via proton transfer from H3O s droplets, mass-analyzed, and detected within 1 ms. The before it becomes hydrated. Thermochemical considerations ( ) þ PC OH 2 ESI-MS signals detected in these experiments suggest that most nonalkane gases could be similarly proto- therefore correspond to species produced on the outermost nated on the surface of pH < 4 water, albeit, perhaps, at layers of the microjet upon brief exposure to PCOOH(g).5,33 different rates. Competitive substrate protonation versus We had previously verified that this setup operates as a hydration at water-hydrophobic media interfaces is the key þ( ) 35 linear transfer device, that is, ESI-MS signals are directly condition for H3O s to manifest itself as a superacid.

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( ) Figure 1. Protonation of hexanoic acid PCOOH on water. Figure 2. ESI mass spectrum of hydronated hexanoic acid, m/z = þ m z þ þ þ PCOOH2 ESI-MS / =117 signalþ intensities as functions of pH. 117 [PC(OH) ],118[PC(OH)(OD) ], and 119 [PC(OD) ],onH O/ Blue circles: Signals from PCOOH produced on aqueous micro- ( ) 2 2 (2 ) (2 ) μ D2O 5/95 microjets at pD = 3.2 exposed to 77 ppbv PCOOH g . jets exposed to 77 ppbv PCOOH g for 10 s. The blueþ line is a See text for details. titration curve with pH1/2 = 2.5. Tan triangles: PCOOH2 signals from 1 mM PCOOH(aq) microjets. All experiments are in 1 atm of N2(g) at 293 K.

Scheme 2. Protonated Hexanoic Acid Tautomers (A and B) and the Product (C) of Their Collisionally Induced Dissociations (CIDs)

In this regard, we would like to point out that the probability of ( ) CH3COOD H-isotope exchange on neutral H2O l is larger than that of its uptake,36 suggesting that the hydration of polar Figure 3. Kinetic isotope effects (KIEs) for the hydronation of acetic acid is already slower than interfacial H-exchange. ( ) ( ) gaseous hexanoic acid PCOOH on H2O/D2O 5/95 microjets In our experiments, PCOOH(g) protonation via reaction R3 exposed to 77 ppbv PCOOH(g) as functions of pD. Tan downward 37 ( ) I I ( ) leads to oxonium (A) or carboxonium (B) species, which triangles and curve: KIE = 95/5 117/ 118 corrected .Blueupward 0 ( ) I ( ) I ( ) fragment to the oxonium C (m/z =89) via neutral CO losses triangles and curve: KIE = 95/5 118 corrected / 119 corrected . þ See text for details. (Scheme 2)38 rather than into the acylium PCO (m/z = 99, 39 0 0 not shown) plus H2O, as reported elsewhere. Noticeably, KIE = F /0.053 values calculated from the ratio F0 ( )( )þ ( ) þ ( ) ( ) Figure 2 shows the mass spectrum obtained by exposing =PCOH OD /PC OD 2 = I11 8 corrected /I11 9 corrected ( ) [ ( ) þ H2O/D2O 5:95 microjets at pD = 3.2 pD = pH measured become increasingly larger than KIE at lower pD, revealing 0.4] to PCOOH(g). It is apparent that the ratio of the that proton transfer becomes progressively faster than F ( ) þ ( )( )þ ≈ isotopologues' raw signals, =PCOH 2 /PC OH OD (neutral) H-atom exchange in more acidic water. 2.78, is much larger than that expected from the ratio of Our observations are consistent with the direct protonation H/D abundances, H/D = 5/95 = 0.053, or from a process of PCOOH(g) on the surface of water by minimally hydrated 40 þ displaying a normal kinetic H-isotope effect KIE < 12, H3O (s)(Figure 4). The thermochemistry of reaction R1 F <12 0.053 = 0.64. Notice that I11 9 :I11 8 :I11 7 /1:0.105: ultimately merges into that of reaction R2 via to the cumula- ( ) þ 0.003 signal intensities should be expected for fully ex- tive hydration energy differences between H2O n 3 H3O and ( ) ( ) þ 28 changed hydronated PCOOH. KIE values, KIE = 0.053 H2O m 3 PC OH 2 cluster ions. The exothermicity/exoergi- F( ) (Δ ≈ Δ ≈ ) corrected , calculated from ratios of corrected experimen- city S1 S2 0 of reaction R1 gradually decreases F( ) ( ) (F ) tal signal intensities, corrected = I11 7 /I11 8 corrected ,as as conditions shift from gas-phase w =0 to bulk water ( ) (F -3) functions of pD are shown in Figure 3. I11 8 corrected takes w=1 g cm . The final outcome is that proton exchange 13 into account the C contribution of I11 7 to I11 8 signals, between fully hydrated species becomes endothermic/ ( ) ( ) - ( ) I11 8 corrected = I11 8 measured 0.065 I11 7 measured . endoergic. In essence, the protonation of PCOOH(aq) requires

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to/from interfacial acceptors/donors. Because acidity is essentially a relative concept, it is not immediately obvious how the protonating ability of water's surface could be deduced from its structure. In plain terms, water's surfaces are not more or less acidic than bulk water, and the degree of protonation/deprotonation of specific species on water's surfaces is not univocally determined by their molecular configurations. Enzyme function arises not only from the structure of their active sites but from the nature and role of near-surface water.53 Attempts at deducing the acidity of water's surface from its structure are therefore akin to expecting to hear the sound of one hand clapping. The KIE associated with the hydronation of PCOOH(g) at the air/water interface is about an order of magnitude larger than that expected from semiclassical transition-state theory - for gas-phase reactions, KIE < 12.54 57 Rigorous analysis of kinetic isotope effects in homogeneous liquid phases involves, Figure 4. Enthalpy diagram for the protonation of hexanoic acid þ however, extensive conformational averaging of solvent PCOOH by H3O under increasing solvation. Data adapted from 40 28 modes. A self-consistent interpretation of the KIE results Meot-Ner, by assuming (1) similar solvation enthalpies for protonated hexanoic acid-water and protonated acetic acid-water of Figure 3 of proton transfer at the air-water interface should ( ) ΔH ( þ( )) - -1 41,46 clusters and 2 hydration H3O g = 115 kcal mol . deal, in addition, with decreasing solvent participation along the reaction coordinate. Such a task is beyond the scope of this strongly acidic conditions because the hydration energy of report,58 but we notice that proton transfers in enzymatic Δ ( þ) - -1 41 59 hydronium Hhyd H3O = 115 kcal mol , significantly reactions often display “abnormally” large KIEs and hint ( ) þ 24,42 exceeds those of larger ions, such as PC OH 2 . A that this circumstance may be associated with the steep water þ( ) similar situation will develop whenever H3O s encounters density gradients in which they take place. The increasingly 43 proton acceptors on the surface of pH < 4 water. The vast larger and diverging KIE and KIE0 values observed at lower pH 26 database on gas-phase proton affinities anticipates that further suggest that these behaviors could result from proton þ( ) H3O s could protonate both strong bases, such as trimethyl- transfers across progressively thinner reaction barriers as 5 þ ( þ ) ( ) amine pKBH =9.8 , and very weak ones, such as PCOOH aq H3O (s) emerges to the outermost water layers. Within the ( þ - ) pKBH < 3 , alkenes and carbonyls, that is, the protonating context of present findings, previous statements in the litera- þ( ) þ( ) potential of H3O s greatly exceeds that of H3O aq of the ture reflecting that “most reactions that take place in solution same acidity. Because the protonation of carboxylic acids in do not occur in the gas phase and vice versa”and that “clearly, 31,37 þ condensed media requires superacidic conditions, H3O - a quantitative knowledge of solvation forces might lead to the ( ) s formally behaves as a superacid in present experiments. understanding and manipulation of enormous new areas of Thus, phenomenological evidence, thermodynamics, and chemistry”43 and that “it is a common misconception to the fact that the isoelectric point of water falls in the 2 < consider enzymatic reactions as actually taking place `in 44 - pH < 4 range at all inert hydrophobic interfaces suggest water'”3,12,14,15,59 61 seem apropos and more farsighted than that the protonation of neutral species approaching water ever. from hydrophobic media should be a general phenomenon. Summing up, we report that gaseous hexanoic acid mole- At this point, it should be apparent that the statements cules are readily protonated upon collision with the surface of “ ” hydronium emerges to the surface of pH < 4 water and mildly acidic pH < 4 water in a process that displays exceed- “ ” interfacial hydronium behaves as a superacid are not ingly large kinetic H-isotope effects. We ascribe these phe- contradictory because they refer to different phenomena. nomena to the action of minimally solvated interfacial The negative charge of droplets and bubbles above the hydronium as “superacidic” proton donors and suggest that isoelectric point strictly implies that hydroxide approaches they may be common to chemistry at water interfaces with ( the air/water interface closer than hydronium by reasons most hydrophobic media. that have been analyzed elsewhere)44,45 but provides no evidence about whether hydronium or hydroxide are available SUPPORTING INFORMATION AVAILABLE Additional data to incoming proton acceptors/donors. Whether the surface of and experimental details. This material is available free of charge water is basic in the 4 < pH < 7 range, that is, whether it can via the Internet at http://pubs.acs.org. accept protons from strong and weak acids, remains to be 5 demonstrated experimentally. AUTHOR INFORMATION The water's surface is not a “surface” but a highly inhomogeneous, discrete layer where water density vanishes within a Corresponding Author: nanometer. Therefore, the presence of hydronium/hydroxide *To whom correspondence should be addressed. ions somewhere in the interfacial layer, as inferred from 47-52 calculations or surface-specific spectroscopies, does ACKNOWLEDGMENT S.E. appreciates the Japan Society for the Pro- not imply that these species can actually proton transfer motion of Sciences Postdoctoral Fellowships for Research Abroad.

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