Is a Methyl Group Always Hydrophobic? Hydrophilicity of

ARTICLE pubs.acs.org/JPCB

Is a Methyl Group Always Hydrophobic? Hydrophilicity of Trimethylamine-N-oxide, Tetramethyl Urea and Tetramethylammonium Ion Yoshikata Koga,*,†,‡ Peter Westh,§ Keiko Nishikawa,^ and S. Subramanian† †

Department of Chemistry, The University of British Columbia, Vancouver, BC Canada V6T 1Z1 Suiteki Juku (Water Drop Institute), Vancouver, BC Canada V6R 2P5 § NSM Research for Functional Biomaterials, Roskilde University, Roskilde DK-4000 Denmark ^ Graduate School of Advanced Integration Sciences, Chiba University, Chiba 263-8522 Japan ‡

ABSTRACT: We have developed what we call the 1-propanol(1P) probing methodology. By using it, we determined the relative hydrophobicity/hydrophilicity indices of 2-butoxyethanol, a typical hydrophobe; urea, a typical hydrophile; and trimethylamine-N-oxide, an amphiphile. By comparing these indices with those for other solutes studied earlier, including tetramethyl urea, tetramethylammonium ion, mono-ols, and polyols, we suggest that methyl groups attached to an N atom, or Nmethyl groups, do not promote hydrophobicity but, rather, enhance hydrophilicity.

’ INTRODUCTION The terms hydrophobicity and hydrophilicity are loosely understood on the basis of human experiences. A third grade school girl asked, “How come oil does not mix with water but vinegar does?” while sprinkling a dressing over her dish of salad. In terms of thermodynamics, the sign and the value of the free energy of hydration is commonly used as the index of hydrophobicity/ hydrophilicity.1a,b Although free energy, G, dictates the overall fate of an equilibrium system, more detailed information is revealed in the derivative quantities of G with respect to the independent variables, (T, p, ni), where ni is the molar amount of the ith component. The higher the order of the derivative, the more clearly subtleties in the interactions will stand out.2a Indeed, the first derivative of G with respect to T separates out H and S, which provide a more detailed physical information of the system than G alone. Further differentiation by T yields heat capacity, Cp, a second derivative of G, which is related to fluctuation in S and H.2b We have utilized this principle to obtain a more detailed picture of intermolecular interactions in aqueous solutions.2b,c In a series of our studies of binary aqueous mono-ols,2b,3 we learned the effect of hydrophobic moieties on the molecular organization of H2O by varying the size of the alkyl group. We concluded that hydrophobes form hydration shells around themselves. The hydrogen bond probability within the hydration shell is enhanced more than that of pure H2O. This resembles the classical “iceberg formation” concept, but more importantly, the hydrogen bond probability of bulk H2O away from hydration shells is reduced progressively as the composition of solute increases. Below the threshold composition, crucially dependent on the size (strength) of hydrophobicity, the connectivity of the r 2011 American Chemical Society

hydrogen bond network is still maintained, or the hydrogen bond percolation is still intact. Hydrophiles, such as urea and polyols, form hydrogen bonds directly to the existing hydrogen bond network of H2O, but the degree of hydrogen bond fluctuation inherent in liquid H2O is retarded, since the H-donor/acceptor symmetry enjoyed in pure H2O is broken by the presence of hydrophilic molecules. The threshold up to which this mixing scheme is operative is ∼0.1 in solute mole fraction where bulk H2O runs out.2c-e In the solute-rich region in aqueous solutions, solute molecules tend to cluster together just as in their pure state. H2O molecules interact with such clusters individually. This mixing scheme seems generally true, irrespective of hydrophobic or hydrophilic solutes. In the intermediate composition range, H2O loses its hydrogen bond network connectivity, and the solution is a mixture of two kinds of clusters: one rich in H2O, and the other, in solute molecules. These two kinds of clusters are reminiscent of mixing schemes in the H2O-rich and the solute-rich regions. We found that these three mixing schemes are generally observed in aqueous solutions.2b,c We named these mixing schemes mixing scheme I, II, and III from the H2O-rich end. The difference between hydrophobes and hydrophiles therefore manifests itself in mixing scheme I. In turn, the solutes that modify the molecular organization of liquid H2O in the respective manner described above are called hydrophobes and hydrophiles, respectively,

Received: September 1, 2010 Revised: February 2, 2011 Published: March 09, 2011 2995

dx.doi.org/10.1021/jp108347b | J. Phys. Chem. B 2011, 115, 2995–3002

The Journal of Physical Chemistry B within our works. Thus, the concept of hydrophobicity/hydrophilicity is relevant only within mixing scheme I. To quantify the degree of hydrophobicity/hydrophilicity, we have introduced the so-called 1-propanol (1P) probing methodology, which is documented in detail elsewhere2d and briefly sketched out below. It is a thermodynamic study of ternary systems, 1P-sample(S)-H2O, where S is the test sample, the hydrophobicity/hydrophilicity nature of which is to be indexed. As discussed below, this method is based on our finding that within mixing scheme I in which H2O retains its integrity as liquid H2O, the solute-solute interactions are H2O-mediated. This is true even between different kinds of solutes, as long as the system is within mixing scheme I.2b,2c Thus, if the presence of S modifies H2O within mixing scheme I, the 1P-1P interaction is mediated via bulk H2O that is subjected to the specific modification by the presence of S, depending on the nature of S. Hence, if we have an indication of the degree of 1P-1P interaction, HE1P-1P as described below, it would reflect the manner in which S induces a change on the bulk H2O. In turn, by observing the induced changes in the 1P-1P interaction S’s effect toward H2O will be identified. Furthermore, the observed rate of the effect on the 1P-1P interaction with a unit addition of S would quantify the strength of S’s specific effect on H2O.

’ 1-PROPANOL(1P)-PROBING METHODOLOGY We experimentally determine the excess partial molar enthalpy of 1P, HE1P, in ternary system 1P-S-H2O. This quantity is defined as E ð1Þ DH E =Dn1P H1P where HE is the excess enthalpy of the mixture. n1P is the molar amount of 1P. The differentiation is performed keeping the molar amounts of H2O, nW; and S, nS, constant. The values of HE1P can be experimentally determined by titrating a small enough amount of 1P into a large amount of solution, N (= n1P þ nS þ nW),2f for a given initial mole fraction of S prior to adding 1P, x0S = nS/(nS þ nW). According to the definition, eq 1, HE1P is the effect of an infinitesimal increase in n1P on HE. It signifies therefore the actual contribution of 1P to HE, or the actual enthalpic situation of 1P in terms of enthalpy in the complex system. Thus, HE1P is a holistic result of many-body interactions operative in the solution. We stress that HE1P is the second derivative of G, and it contains more detailed physical information than HE, the first derivative quantity. However, as mentioned above, it does not provide as detailed information as a third derivative of G would. We therefore take one more derivative of HE1P with respect n1P and call it the 1P-1P enthalpic interaction, HE1P-1P, defined as2b,c,3 E E E ð2Þ H1P-1P N DH1P =Dn1P ¼ ð1-x1P Þ DH1P =Dx1P which is the third derivative of G and should contain more detailed information than HE1P. Its physical meaning is the effect of incoming 1P on the actual enthalpic situation of existing 1P. Hence, we call it the 1P-1P enthalpic interaction. This quantity is more sensitive to any change in the aqueous solutions than HE1P, as will become evident in the Results section. In evaluating HE1P-1P, we use graphical differentiation without resorting to any fitting function. Thus, HE1P-1P is completely model-free. The isobaric thermal expansivity, Rp, is another second derivative of G and is related to the entropy-volume cross fluctuation. We earlier defined the normalized entropy-volume

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cross fluctuation, SVΔ, as2b,e,4 SV

Δ RTRp =Vm

ð3Þ

where R is the gas constant and Vm is the molar volume of the solution. As discussed extensively elsewhere,2e,4 this quantity provides qualitative information about the intensity and the extensity of S-V cross fluctuation. For a normal liquid, Rp and, hence, SVΔ is always positive, whereas that of liquid H2O contains a negative contribution due to hydrogen bonding. Thus, if one could identify the negative contribution part and its x1P dependence, the effect of solute 1P on the integrity of H2O could be detected. The next composition derivative, therefore, could indicate the effect of the solute on SVΔ more directly. We define the partial molar normalized S-V cross fluctuation of 1P, SVΔ1P, as SV Δ 1P ð1 - x1P Þ DSV Δ=Dx1P ð4Þ which is a third derivative of G. Figure 1a shows the plots of experimentally determined HE1P-1P and SVΔ1P against x1P in the binary 1P-H2O. The ordinate for SVΔ1P is scaled by a single factor. The figure indicates the x1P dependence of both quantities scales exactly. This means that the 1P-1P enthalpic interaction, HE1P-1P, and the partial molar normalized S-V cross fluctuation of 1P, SVΔ1P, share the same fundamental cause. We therefore suggested that within mixing scheme I, the 1P-1P enthalpic interaction is operative via bulk H2O away from solutes, where the fluctuations are dominant.2b,c,e,4 As is evident in the figure, HE1P-1P and SVΔ1P show a peak type anomaly. This peak type anomaly is a hallmark of a hydrophobic 1P.2b,3 Up to point X in Figure 1a, mixing scheme I is operative. Beyond point Y, mixing scheme II sets in, and H2O is no longer a collective entity or loses its integrity as liquid H2O. The top of peak, point X, is the onset, and point Y, the bottom of the downhill slope, is the end point of the transition from mixing scheme I to II. Since the 1P-1P enthalpic interaction is operative via bulk H2O away from solutes within mixing scheme I, when a third component (S) is added and then HE1P-1P is determined, its x1P dependence pattern should reflect the modification to the bulk H2O by the presence of S. Indeed, our previous trials with various kinds of S indicate that when a hydrophobic S as strong as the probing 1P is present, the HE1P-1P pattern is modified typically as in case A in Figure 1b. Namely, the peak shifts parallel to the west. This is quite understandable in that the presence of S perturbs H2O in the same way as 1P would a part way toward point X, and 1P is now required to drive the system only a remaining way to point X. But if the hydrophobicity of S is stronger (or weaker) than the probing 1P, the locus of point X shifts farther (or less) to the west, as in case C (or B) in Figure 1b. The degree of this westward shift was found linear to x0S, and thus, its proportionality constant (slope) shows an index of the hydrophobicity and the degree of hydration, the hydration number. Namely, this slope gives the number of H2O molecules that hydrate a hydrophobic S and are made unavailable for 1P to interact with. At the same time, depending on the strength of hydrophobicity, point X shifts to the north (or the south), as well, as in case C (or B) in Figure 1b. As we saw in Figure 1a, the x1P dependence of HE1P-1P and that of SVΔ1P are identical, with a single scaling factor, and the north-/southward shift of point X should be related to an increase/decrease in SVΔ1P; that is, the extent of fluctuations in the bulk water. As discussed above, SVΔ contains a negative contribution due to the hydrogen bonding prevalent in 2996

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The Journal of Physical Chemistry B

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H2O or aqueous solutions within mixing scheme I. The increase in SVΔ on addition of 1P could reflect the decrease in the H2O integrity due to the presence of 1P. Thus, the westward shift in Figure 1b is related to the hydration and the north-/southward one contains information about how the hydrogen bond probability of bulk H2O away from hydration shell decreases. When S is a hydrophile, the HE1P-1P pattern changes are shown in Figure 1c. Point X moves southward only. We suggested, therefore, that a hydrophile forms hydrogen bonds directly to the existing network of H2O and, hence, does not alter the hydrogen bond connectivity. However, its presence as an impurity within the network retards the positive (normal) part of S-V cross fluctuation. An amphiphile moves point X southwest, as shown in Figure 1d, and the westward and southward components indicate the hydrophobic and hydrophilic contributions, respectively. Thus, in this manner, the details of an amphiphile’s effect can be identified. For all cases studied so far, the westward or the north-/ southward shifts of point X were found to scale linearly with the initial mole fraction of S, x0S, and the slopes were suggested, as mentioned above, to identify the hydrophobicity or hydrophilicity of S. In addition, we calculate a hydration number from the slope for hydrophobicity (the westward shift).2d We note in passing the existence of a part of H2O with much slower dynamics than that of pure H2O has been identified by femtosecond nonlinear spectroscopic studies in aqueous solutions of ionic compounds5 and nonelectrolytes,6 hinting at the existence of hydration shells around solute molecules, ions, or nonelectrolytes. Here, we apply this 1-P probing thermodynamic methodology for aqueous solutions of tri-methylamine-N-oxide (TMAO), urea (UR), and 2-butoxyethanol (BE).

’ EXPERIMENTAL SECTION 1-propanol (>99.8%,Fluka) and TMAO (>99%, Fluka Buchs, Switzerland) were used as supplied for TMAO studies. Urea (Sigma, ACS reagent, >99.0%), BE (Aldrich, >99.9%), and 1-propanol (ACROS, >99.5%) were used as supplied for UR and BE runs. Due care was exercised to avoid contamination by atmospheric moisture. The excess partial molar enthalpy of 1P was determined by using a TAM-2277 titration calorimeter (Thermometric, now TA Instruments, New Castle, DE) for 1P-TMAO-H2O series. For the other two series, 1P-UR-H2O and 1P-BE-H2O, a home-constructed titration calorimeter of a design similar to LKB 8700 was used.2f For both cases, we made sure that the ratio of the amount of titrant 1P over that of titrand was small enough for a good approximation for HE1P.7 The detail of appropriate graphical differentiation to evaluate HE1P-1P by eq 2 has been described elsewhere.8

Figure 1. (a) HE1P-1P and SVΔ1P against x1P for 1P-H2O. The ordinate for SVΔ1P is scaled by a single factor. (b) x1P dependence pattern of E H1P-1P in 1P-S-H2O for S = hydrophobes for a unit increase of x0S. (c) x1P dependence pattern of HE1P-1P in 1P-S-H2O for S = hydrophiles for a E unit increase of x0S. (d) x1P dependence pattern of H1P-1P in 1P-S-H2O for S = an amphiphile for a unit increase of x0S. See text.

’ RESULTS Plots of HE1P data against x1P are shown in Figure 2. Addition of TMAO (Figure 2a), UR (Figure 2b), and BE (Figure 2c), seems to induce qualitatively different effects on the HE1P plots. The detailed trends of these differences among different test samples will stand out more clearly in the third derivative, HE1P-1P, which is shown in Figure 3. Figure 3a indicates, in comparison with Figure 1d, that TMAO is clearly an amphiphile. Its westward and southward components were found linear to the initial mole fraction of TMAO, x0TMAO. Their slopes were taken as indices for 2997



Figure 2. (a) Excess partial molar enthalpy of 1P in 1P-TMAO-H2O at 25 C. x0TMAO is the initial mole fraction of TMAO of the mixed solvent, into which 1P is successively titrated. (b) Excess partial molar enthalpy of 1P, HE1P, in 1P-UR-H2O at 25 C. x0UR is the initial mole fraction of UR in the mixed solvent UR-H2O, into which 1P is titrated. (c) Excess partial molar enthalpy of 1P in 1P-BE-H2O at 25 C. x0BE is the initial mole fraction of BE in the mixed solvent BE-H2O, into which 1P is successively titrated.

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Figure 3. (a) The 1P-1P enthalpic interaction, HE1P-1P, for 1PTMAO-H2O at 25 C. The rates of the westward and southward shifts of point X per x0TMAO indicate the strength of hydrophobicity and that of hydrophilicity, respectively. (b) The 1P-1P enthalpic interaction, E H1P-1P , in 1P-UR-H2O at 25 C. UR being a typical hydrophile, there is no westward shift. (c) The 1P-1P enthalpic interaction, HE1P-1P, in 1P-BE-H2O at 25 C. Open symbols indicate δxBE = 0.002, and solid symbols indicate δxBE = 0.004 in taking the derivative. See text. 2998



Figure 4. Southward shift of point X in Figure 3b for 1P-UR-H2O. Solid circles are from this work, and open circles are earlier data.25 The figure indicates that the hydrophilic effect of UR slows down by about 3-fold suddenly at xUR = 0.08, hinting that UR forms a trimer in aqueous solutions in this range from 0.08 to at least 0.2.

hydrophobicity and hydrophilicity, as discussed above and plotted in Figure 5. For urea (UR), Figure 3b shows a hallmark for a hydrophilic solute (Figure 1c). We noted, however, that at the initial mole fraction of UR, x0UR = 0.23338, the HE1P-1P pattern did not show a peak type anomaly any longer and is not shown in Figure 3b. Indeed, our previous work on binary UR-H2O suggested that beyond x0UR > 0.2, the mixing scheme changed drastically.9 We thus suggested that in this concentration region, the system is already in mixing scheme II.9 The southward shifts of point X in Figure 3b are plotted against x0UR in Figure 4. The slope of these plots provides the index for hydrophilicity for UR. There is a clear break in the slope at ∼x0UR = 0.08. As is evident from Figure 3b, the peak anomaly is retained up to at least x0UR = 0.1838, and thus, regardless of its origin, this behavior at 0.08 must be related to that of UR. We suggested that UR aggregates at this concentration without destroying the integrity of H2O.9 The aggregate is most likely to be a trimer, judging from roughly a 3-fold reduction in slope. Here, we limit our consideration of hydrophilicity of UR below x0UR < 0.08, since we are interested in the effect of unassociated UR on H2O. The results are shown in Table 1 and plotted in Figure 5, together with the earlier data for other pertinent samples. Figure 3c indicates clearly that BE is a hydrophobe. Here again, the HE1P-1P pattern is of a peak type anomaly, only within mixing scheme I, x0BE g 0.013. As above, the slope of the westward shift against x0BE is taken as an index for hydrophobicity related to hydration propensity. There is no apparent northor southward shift, indicating no retardation of the S-V cross fluctuation. This could be a special case because of the ether -O- present in the BE molecule.

’ DISCUSSION AND CONCLUSION In Figure 5, the abscissa is the slope of the westward shift per unit increase in x0S, which is defined as an index of hydrophobicity closely related to the hydration number. The ordinate is that of

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Figure 5. Hydrophobicity/hydrophilicity map by the 1P-probing methodology. The westward direction indicates hydrophobicity or hydration propensity. The southward shows hydrophilicity, and the northward hydrophobicity or fluctuation nature. The farther away from the origin, the stronger is the propensity. See Table 1 for the symbols (A, B, C, etc.) on the map.

the south- or northward shift, which we use for an index of hydrophilicity or hydrophobicity in terms of the effect on the S-V cross fluctuation. The dual appearance of hydrophobicity on both axes has bearings to our findings that the effect of a hydrophobe on H2O is two-fold: to form the hydration shell in the immediate vicinity and to reduce the hydrogen bond probability of bulk H2O away from the hydration shell. The sample species, their abbreviation and their marks on the map, the values of indices, and references are given in Table 1. In Figure 5, H2O defines the origin of the map, and the probing 1P is necessarily placed at point B (-1, 0). This set of loci provides the reference point to which the relative hydrophobicity/hydrophilicity (relative to the probing 1P) of each species is given. The distance from the origin indicates the strength of each propensity. Amphiphiles spread out in the southwest direction on the map. The loci of mono-ols in Figure 5 span from ME (symbol “E” on Figure 5) to TBA (D) monotonically and to BE (Z), 2-butoxyethanol. The northward trend is broken between TBA and BE probably due to the presence of ether -O- in BE. The distance from the origin identifies the relative hydrophobicity of the mono-ols in the increasing order ME (E) < 2P (C) < 1P (B) < TBA (D) < BE (Z). This is consistent with our suggestion based on the comparative behavior of third derivative quantities in binary aqueous mono-ols.2g The effect of a methyl group appears more subtle, however, in comparison between 1P and 2P. The fact that 2P is a little more hydrophilic than 1P may reflect the weak electron-donating propensity of the methyl group. On the other hand, the relative loci of 12P (1,2propendiol) (P) and 13P (1,3-propanediol) (Q) indicates the methyl group is definitely more hydrophobic than -CH2OH. The overall hydrophobicity could also be influenced by the adjacent presence of an -OH group. Indeed, glycerol (Gly) and ethylene glycol (EG) are at the identical spot at R on the map, suggesting almost complete compensation between the effects of nonmethyl C and OH. Thus, the overall hydrophobicity of alkyl 2999



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Table 1. The Hydrophobicity/Hydrophilicity/Hydration Number Indices mark in Figure 1

sample

abbreviation

hydrophobicity westward

hydration

hydrophilicity southward

applicable range in mole

slope

number

slope

fraction

0

refb

A

H2O

B

1-propanol

1P

-1

19

0 0

0-0.049

C

2-propanol

2P

-0.8

15

-170

0-0.050

26a

D

tert-butanol

TBA

-1.44

28

940

0-0.045

26b

E

methanol

ME

-0.21

3

-900

0-0.07

26c

F

trimethylamine-

TMAO

-0.35

6

-330

0-0.04a

this work

M

N-oxide NH4þ

NH4þ

-0.05

1(1

0

0-0.09a

26d

NMe4þ

0

-1200

0-0.08a

26d

0-0.08

this work

0.08-0.2

this work

þ

H

N(CH3)4

J

urea(monomer)

UR

0

-1210

urea(trimer)

UR

0

-390

K

tetramethyl urea

TMU

-0.63

12

-3400

0-0.08

26e

L

acetone

AC

-0.58

11

-1450

0-0.08

26e

P

1,2-propanediol

12P

-0.52

10

-790

0-0.075a

26f

Q R

1,3-propanediol glycerol

13P Gly

-0.43 -0.17

8 2.5

-1020 -1180

0-0.05a 0-0.10

26f 26g

R

ethylene glycol

EG

-0.17

2.5

-1100

Z

2-butoxyethanol

BE

-2.83

57

0

0-0.11

26c

0-0.017

this work

a

The applicability range is minimum possible. The upper limit could be higher. The 1P-probing was applied to the upper limit indicated here without losing the integrity of H2O. b The ranges of applicability without a footnote are given collectively in Table V-3 (p 114) and VI-3(p 159) of ref 2a.

groups is also influenced by an adjacent hydrophilic atom. The methyl groups discussed so far are attached to a C atom, except for methanol, and we identify them as “C-methyl”. Relative to this alcohol series, the locus for TMAO (F) on the map is surprisingly close to the origin (H2O). We showed earlier that the effective “osmolytes” in various organisms under water stress are close to the origin in this map.10 TMAO is apparently one of the effective osmolytes, together with trehalose.10,11 We note there are two more sets of equally surprising results in the map involving the N-methyl groups. Comparisons of the loci of NH4þ (M)12 and N(CH3)4þ (H), for example, show that replacing H- with CH3- does not increase hydrophobicity but, in fact, makes it more hydrophilic! Comparing urea (J) with tetramethylurea (K) reveals that the four N-methyl groups has little effect on hydrophobicity just to a level below 2P (C), but it increases hydrophilicity to point K. TMU apparently gains hydrophobicity a little while its hydrophilicity is much larger than UR. On replacing both NH2- on UR with CH3-, the resulting acetone (AC) at L retains about the same hydrophilicity as UR, but AC’s hydrophobicity increases to a little less than that for 2P (C). This suggests that the hydrophilic effects of NH2- in UR is marginal in comparison with that by >CdO. Thus, we point out within our 1P-probing methodology that N-methyl groups that we discussed here do not promote hydrophobicity but, rather, do enhance hydrophilicity. Although these findings seem surprising at first sight, they may be rationally understood in the following manner. Starting with comparison between NH4þ and N(CH3)4þ, hydrogen in NH4þ is highly acidic due in part to a higher electronegativity of N than C, particularly so in an aqueous environment. It is readily neutralized by a single H2O, as indicated by the hydration number 1 ( 12d (see Table 1). The influence of a positive charge is thus of short range. In N(CH3)4þ, on the other hand, the central positive charge is protected from direct contact with H2O. The protected charge

on N in the hydrophobic pocket induces dipoles on the surrounding many H2O molecules, which in turn encourages hydrogen on methyl groups to form hydrogen bonds with H2O. Such weak hydrogen bonds involving N-methyl groups have been suggested earlier.13a,b Thus, N(CH3)4þ acts purely as a hydrophile, at point H on the map. For UR (J), our observation suggested that the hydrophilicity of NH2- itself is marginal. Thus, upon replacing an amino group with a methyl group, the resulting AC (L) does not lose hydrophilicity and gains hydrophobicity as much as expected for the one with two methyl groups, close to 2P (C). When hydrogen on an amino group is replaced by methyl, not only is hydrophobicity lower than expected for four methyl groups, but hydrophilicity also increases drastically (point K). The difference between AC and TMU is no doubt due to the difference between C-methyl and N-methyl. In addition to higher electronegativity of N, the latter has a lone pair on a nonbonding π orbital. This enhances the electron-donating tendency of Nmethyl further, resulting in an ease of making hydrogen bonds to surrounding H2O via methyl hydrogen atoms. A similar scenario could underlie the low hydrophobicity and low hydrophilicity of TMAO. In aqueous media, TMAO is more likely to be in the form (CH3)3Nþ-O-, and CH3-’s electrondonating propensity is even more enhanced by the positive charge on N. Hence, N-methyl groups do not enhance hydrophobicity. The hydrophilicity of O is strong, but overall, TMAO turns out to be amphiphilic with weak hydrophobicity and equally weak hydrophilicity. We therefore suggest that N-methyl is not strongly hydrophobic in aqueous solutions. In this regard, we note recent observations on S-methyl groups having the same tendency to donate electrons toward S,14a,b which, indeed, has a lone pair. Clearly, further theoretical investigation on the interaction of H2O with N-methyl groups as well as the genuinely hydrophilic parts are required. There are, indeed, theoretical studies comparing TBA and TMAO in aqueous solutions,15a,b but their focus is on the interaction of H2O with hydrophilic ends. 3000



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hydration shell is lowered gradually. As discussed above, we have experimental evidence that the hydrogen bond probability within the hydration shell is higher than that of pure H2O for hydrophobic S,2b but for S = NaCl, we have not yet obtained such data. Our similar studies on Na salts of other halides,2d,20,21 along with an X-ray scattering22 and theoretical studies,23,24 indicated that the hydration number of Naþ is 5.2. If so, the hydration number of Cl- is therefore 2.3,2d,21 assuming that NaCl is completely dissociated. The fact that the westward shift of point X vs x0S (S = NaCl) is linear within the concentration range studied may support the assumption, though indirectly. These findings for Naþ and Cl- could be utilized for characterizing individual ions in aqueous solutions. Namely, if we choose Naþ or Cl- for the counterion, and apply the 1P-probing methodology for the resulting salt, the character of the ion in question can then be determined by subtracting that of the chosen counterion (Naþ or Cl-) from the result of the salt.

’ AUTHOR INFORMATION E Figure 6. The x0S dependence of H1P-1P in 1P-S-H2O for S = NaCl. See text.

We stress in closing that the present methodology suggests that methyl groups are not always a source of hydrophobicity. In particular, N-methyl groups rather promote hydrophilicity due most likely to a high electronegativity of N and the presence of a lone pair on N. C-methyl groups, C having much less electronegativity and without a lone pair on the central C, promote hydrophobicity. Thus, recent criticism of the classical “iceberg” concept based on compounds with N-methyl groups6,16a,16b must be evaluated with caution. However, a recent femtosecond midinfrared study17 recognized a large quantitative difference in the aggregation behaviors of TMAO and TBA in mixing scheme II. Another point we would like to stress regarding the original “iceberg” concept18 is that Frank and Evans used the partial molar entropy data at infinite dilution, and thus, the concept was intended only in this limited range. We have proposed2b,19 that the “iceberg” concept is basically correct, with a concomitant decrease in the hydrogen bond probability of bulk H2O away from hydration shells and that the concept is applicable within a finite H2O-rich region only. Such upper limits of applicability are listed elswhere2b,c and also listed in Table 1. When studying aqueous solutions of “hydrophobes”, attention must be paid to choose a proper sample and within the proper mole fraction limit.

’ APPENDIX Figure 6 shows the HE1P-1P pattern for S = NaCl.2d,3,20,21 In the presence of NaCl, point X shifts to the west, indicating hydration as for the case of hydrophobic S. Namely, a number (to be calculated from the slope of the westward shift vs the initial mole fraction of NaCl) of H2O molecules hydrate a pair of Naþ and Cl- ions and are made unavailable for 1P to interact with. In addition, we note that there is no change in the north-south position of X and that the value of HE1P-1P for x1P = 0 is also unchanged. The latter observation suggests that although NaCl is hydrated, the bulk H2O away from the hydration shell remains unperturbed, and the hydrogen bond probability is the same as in pure H2O. This is in contrast to the case for hydrophobic S, in which the hydrogen bond probability of bulk H2O away from

Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT This work was supported by NSERC of Canada; the Danish Research Agency (Grants 26-02-0160 and 21-04-0087); and the Ministry of Education, Culture, Science and Sports of Japan. ’ REFERENCES (1) (a) Underwood, R.; Tomlinson-Phillips, J.; Ben-Amotz, D. J. Phys. Chem. B 2010, 114, 8646. (b) Zhong, Y.; Patel, S. J. Phys. Chem. B 2010, 114, 11076. (2) (a) Koga, Y. Solution Thermodynamics and Its Application to Aqueous Solutions: A Differential Approach; Elsevier: Amsterdam, 2007. Chapter I, Section 8; (b) Chapter V; (c) Chapter VI; (d) Chapters VII and VIII; (e) Chapter IV; (f) Chapter III; (g) p 114. (3) Koga, Y.; Nishikawa, K.; Westh, P. J. Phys. Chem. B 2004, 108, 3873. (4) Koga, Y. Can. J. Chem. 1999, 77, 2039. (5) Omta, A. W.; Kropman, M. F.; Woutersen, S.; Bakker, H. L. Science 2003, 301, 347. (6) Rezus, Y. L. A.; Bakker, H. L. Phys. Rev. Lett. 2007, 99, 148301. (7) Koga, Y. In Copmrehensive Handbook of Calorimetry and Thermal Analysis; Sorai, M., Ed.; John Weiley and Sons: New York, 2004; p195. (8) Parsons, M. T.; Westh, P.; Davies, J. V.; Trandum, Ch.; To, E. C. H.; Chiang, W. M.; Yee, E. G. M.; Koga, Y. J. Solution Chem. 2001, 30, 1007. (9) Koga, Y.; Miyazaki, Y.; Nagano, Y.; Inaba, A. J. Phys. Chem. B 2008, 112, 11341. (10) Koga, Y.; Nishikawa, K.; Westh, P. J. Phys. Chem. B 2007, 111, 13943. (11) Somero, G. N.; Yancey, P. H.; In Handbook of Cell Physiology; Hoffman, J. F., Jamieson, J. D., Eds.; Oxford University Press: New York, 1997; Vol. 14, pp 441-484. (12) For applying the 1P-probing methodology to an ion, we use Naþ or Cl- as a counterion. We then apply the methodology to the salt. The resulting hydrophobocity/hydrophilicity index is corrected for the contribution from Naþ or Cl-. As shown in the Appendix, Naþ and Clare hydration centers with hydration numbers 5.2 and 2.3, respectively. In addition, we found that neither ion alters the bulk H2O away from the hydration shell. (13) (a) Takahashi, O.; Kohno, Y.; Nishio, M. Chem. Rev. 2010, 110, 6049.(b) Brammer, L. In Crystal Design: Structure and Function, 3001



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