Hydrophobic Effects. Opinions and Facts

The term hydrophobic interactions denotes the tendency of relatively apolar molecules to stick together in aqueous solution. These interactions are of importance in many chemical disciplines, including the chemistry of in vivo processes. Enzyme-substrate interactions, the assembly of lipids in biomembranes, surfactant aggregation, and kinetic solvent effects in water-rich solutions are all predominantly governed by hydrophobic interactions. Despite extensive research efforts, the hydration of apolar molecules and the noncovalent interactions between these molecules in water are still poorly understood. In fact, the question as to what the driving force for hydrophobic intractions is shifts the study into a quest for a detailed understanding of the remarkable properties of liquid water. This review highlights some of the novel insights that have been obtained in the past decade. The emphasis is on both hydrophobic hydration and hydrophobic interactions since both phenomena are intimately connected. Several traditional views have been found to be deeply unsatisfactory, and courageous attempts have been made to conceptualize the driving force behind pairwise and bulk hydrophobic interactions. The review presents an admittedly personal selection of the recent experimental and theoretical developments, and when necessary, reference is made to relevant studies of earlier date.     

Kinetic evidence for hydrophobically stabilized encounter complexes formed by hydrophobic esters in aqueous solutions containing monohydric alcohols.

The pH-independent hydrolysis of four esters, p-methoxyphenyl 2,2-dichloroethanoate (1a), p-methoxyphenyl 2,2-dichloropropanoate (1b), p-methoxyphenyl 2,2-dichlorobutanoate (1c), and p-methoxyphenyl 2,2-dichloropentanoate (1d), in dilute aqueous solution has been studied as a function of the molality of added cosolutes ethanol, 1-propanol, and 1-butanol. The rate constants for the neutral hydrolysis decrease with increasing cosolute concentration. These kinetic medium effects respond to both the hydrophobicity of the ester and of the monohydric alcohol. The observed rate effects were analyzed using both a thermodynamic and a kinetic model. The kinetic model suggests a molecular picture of a hydrophobically stabilized encounter complex, with equilibrium constants K(ec) often smaller than unity, in which the cosolute blocks the reaction center of the hydrolytic ester for attack by water. The formation of these encounter complexes leads to a dominant initial-state stabilization as follows from the thermodynamic model. Decreases in both apparent enthalpies and entropies of activation for these hydrolysis reactions correspond to unfavorable enthalpies and favorable entropies of complexation, which confirms that the encounter complexes are stabilized by hydrophobic interactions.     

The nature of the micellar stern region as studied by reaction kinetics. 2

The nature of rate-retarding effects of cationic micelles on the water-catalyzed hydrolyses of a series of para-substituted 1-benzoyl-1,2,4-triazoles (1a-f) and 1-benzoyl-3-phenyl-1,2,4-triazole (2) has been studied using kinetic methods. A comparison is drawn between medium effects in the micellar Stern region and in model solutions for the micellar Stern region. Simple model solutions involving concentrated aqueous solutions of a small ionic molecule resembling the surfactant headgroup, as reported before,(1) were improved. New model solutions for alkyltrimethylammonium bromide micelles contain both tetramethylammonium bromide (TMAB), mimicking micellar headgroups, and 1-propanol, mimicking hydrophobic tails. The rate-retarding effect of micelles on the hydrolysis of 1a-f and 2 is caused by the high concentration of headgroups as well as by hydrophobic tails in the Stern region where 1a-f and 2 bind to the micelle. Individual contributions of these interactions are quantified. Rate-retarding effects found for different probes, with different sensitivities for interactions as they occur when the probe binds to the micellar Stern region, as well as the micellar Stern region's micropolarity as reported by the E(T)(30) probe, are satisfactorily reproduced by new model solutions containing both TMAB and 1-propanol.     

Hydrophilicity of Polar and Apolar Domains of Amphiphiles

The hydrophilicity of polar and apolar domains of various amphiphiles was systematically estimated for their homologues and analogues by measuring the molar adiabatic compressibility of an aqueous solution at infinite dilution. The homologues of protic alkyl H(CH(2))(n)-, perfluoroalkyl F(CF(2))(n)-, and alkylphenyl H(CH(2))(n)(C(6)H(5))- groups (n=0-10) were chosen to represent apolar hydrophobic domains. The polar hydrophilic domains tested were -SO(4)Na, -SO(3)Na, -COONH(4), -N(CH(3))(3)Br, N(C(m)H(2m+1))(4)Br (m=1-5), and -NH(CH(2))(n)SO(3) (n=3, 4) groups. Also tested were the tetraphenyl ionic compounds (C(6)H(5))(4)MX (M=B/X=Na, M=P/X=Cl, M=As/X=Cl) to study the effect of the ionic sign of the core atom across the tetraphenyl apolar shell, the polyethylene glycols H(OCH(2)CH(2))(m)OH (m=1-4) to study the role of apolar -CH(2)- units in the hydrophilic oxyethylene group, and the zwitterionic dimethylaminoalkylsulfonate (CH(3))(2)NH(CH(2))(n)SO(3) homologues to study the effect of intramolecular salt formation on the hydrophilicity of the zwitterion. The adiabatic compressibility of the solution was calculated from measurement of the sound velocity and density of solutions. The introduction of laboratory automation and the numerical control of the system improved the accuracies and efficiencies of the measurements a great deal. The range of the temperature scan was 0-40 degrees C with an effective accuracy of +/-0.001 degrees C and the concentration was automatically scanned down to far below the cmc of the surfactant. The hydrophilicity of various polar and apolar substances was estimated as the decrease of molar adiabatic compressibility of the aqueous solution with increased concentration of their homologues and analogues. The hydrophobic hydration of nonpolar substances was found to be very small at room temperature and was barely detected above 40 degrees C; however, it became large as the temperature was lowered and attained a maximum at 0 degrees C. The cationic charge of quaternary ammonium N(+)(C(n)H(2n+1))(4) was found to enhance the hydrophobic hydration of methylene groups located at a distance of 4 to 6 ? from the core nitrogen atom, while the terminal negative charge of the anionic surfactant R-SO(4)(-), R-SO(3)(-), or R-COO(-) was found to decrease the hydrophobic hydration of -CH(2)- units within the same range. The hydrophilicity of quaternary ammonium and the tetraphenyl ions should be synergistically given by both hydrophobic and ionic hydrations. The hydrophilicity of the perfluoromethylene unit -CF(2)- was found to have a value comparable to that of the protic methylene unit -CH(2)-. The hydrophobic hydration seems to offer a good measure of the hydrophilicity of apolar substances; however, it does not necessarily represent the "hydrophobicity" of the apolar segment when the "surface activity" of the amphiphile is concerned. Copyright 2000 Academic Press.     

Excess enthalpies of solution of primary and secondary alcohols in dodecyldimethylamine oxide micellar solutions

The excess enthalpies of solution with respect to water of some primary and secondary alcohols in dodecyldimethylamine oxide (DDAO) micellar solutions were measured by mixing aqueous solutions of alcohols with surfactant solutions. Standard free energies, enthalpies and entropies were obtained from the distribution of alcohols between aqueous and micellar phases. It is shown that thermodynamics of transfer of secondary alcohols from aqueous to the DDAO micellar phase differ slightly from those of their corresponding primary alcohols, that the additivity rule holds for free energies of transfer and that enthalpy and entropy display convex curves. The present data are compared with those from the aqueous to the dodecyltrimethylammonium bromide (DTAB) micellar phases and to the literature data for transfer from water to octane. The role of the hydrophilic interactions between OH group and the micellar head groups and of the hydrophobic interactions between the methylene group and its apolar environment is evidenced.     

Effect of substituents on the stabilities of multiply-substituted carbon-centered radicals

The bond dissociation energies (BDEs) and radical stabilization energies (RSEs) which result from 166 reactions that lead to carbon-centered radicals of the type ˙CH(2)X, ˙CHXY and ˙CXYZ, where X, Y and Z are any of the fourteen substituents H, F, Cl, NH(2), OH, SH, CH[double bond, length as m-dash]CH(2), C[triple bond, length as m-dash]CH, BH(2), CHO, COOH, CN, CH(3), and CF(3), were calculated using spin-restricted and -unrestricted variants of the double-hybrid B2-PLYP method with the 6-311+G(3df,2p) basis set. The interactions of substituents X, Y, and Z in both the radicals (˙CXYZ) and in the precursor closed-shell molecules (CHXYZ), as well as the extent of additivity of such interactions, were investigated by calculating radical interaction energies (RIEs), molecule interaction energies (MIEs), and deviations from additivity of RSEs (DARSEs) for a set of 152 reactions that lead to di- (˙CHXY) and tri- (˙CXYZ) substituted carbon-centered radicals. The pairwise quantities describing the effects of pairs of substituents in trisubstituted systems, namely pairwise MIEs (PMIEs), pairwise RIEs (PRIEs) and deviations from pairwise additivity of RSEs (DPARSEs), were also calculated for the set of 61 reactions that lead to trisubstituted radicals (˙CXYZ). Both ROB2-PLYP and UB2-PLYP were found to perform quite well in predicting the quantities related to the stabilities of carbon-centered radicals when compared with available experimental data and with the results obtained from the high-level composite method G3X(MP2)-RAD. Particular selections of substituents or combinations of substituents from the current test set were found to lead to specially stable radicals, increasing the RSEs to a maximum of +68.2 kJ mol(-1) for monosubstituted radicals ˙CH(2)X (X = CH[double bond, length as m-dash]CH(2)), +131.7 kJ mol(-1) for disubstituted radicals ˙CHXY (X = NH(2), Y = CHO), and +177.1 kJ mol(-1) for trisubstituted radicals ˙CXYZ (X = NH2, Y = Z = CHO).     

Polyethylenimine catalysts containing an isolated apolar binding site: Solovolysis of p-nitrophenyl esters

The preparation dodecane-block-poly[ethylenimine-graft-4(5)-methylimidazole] copolymers and related model compounds has been described and such polymers have been described and such polymers have been demonstrated to be efficient catalysts for the hydrolysis of activated phenyl esters in aqueous solutions. Polymeric catalysts that contain isolated apolar blocks exhibited enhanced catalytic activity for the hydrolysis of the p-nitrophenyl esters of acetate and butyrate compared with polymer model compounds. This rate enhancement was atributed to the apolar binding of substrate within the apolar polymer regime. Twenty-to 100-fold increases in the second-order rate constants were observed for the hydrolysis of the longer-chain p-nitrophenyl esters. This is indicative of a significant hydrophobic interaction. The contribution of the apolar block to the hydrophobic interaction was masked in the hydrolysis of the p-nitrophenyl caproate and p-nitrophenyl laurate substrates. In both instances the dominant contribution to the hydrophobic interactions was ascribed to a substrate-imidazole intermediate rather than the apolar block of the catalyst. The pH-rate profiles for the hydrolysis of p-nitrophenyl esters by the various catalysts indicated an absence of any cooperative interactions between imidazole residues or amine groups.     

Kinetics of hydrolysis of 1-benzoyl-1,2,4-triazole in aqueous solution as a function of temperature near the temperature of maximum density,and the isochoric controversy

At temperatures above and below the temperature of maximum density, TMD, for water at ambient pressure, pairs of temperatures exist at which the molar volumes of water are equal. First-order rate constants for the pH-independent hydrolysis of 1-benzoyl-1,2,4-triazole in aqueous solution at pairs of such isochoric temperatures show no unique features. Taken together with previously published kinetic data for the hydrolysis of a range of simple organic solutes in both water and D2O near their respective TMDs, we conclude that special significance in the context of rates of chemical reactions in aqueous solutions should not be attached to the isochoric condition.     

Thermal signature of hydrophobic hydration dynamics

Hydrophobic hydration, the perturbation of the aqueous solvent near an apolar solute or interface, is a fundamental ingredient in many chemical and biological processes. Both bulk water and aqueous solutions of apolar solutes behave anomalously at low temperatures for reasons that are not fully understood. Here, we use (2)H NMR relaxation to characterize the rotational dynamics in hydrophobic hydration shells over a wide temperature range, extending down to 243 K. We examine four partly hydrophobic solutes: the peptides N-acetyl-glycine-N'-methylamide and N-acetyl-leucine-N'-methylamide, and the osmolytes trimethylamine N-oxide and tetramethylurea. For all four solutes, we find that water rotates with lower activation energy in the hydration shell than in bulk water below 255 +/- 2 K. At still lower temperatures, water rotation is predicted to be faster in the shell than in bulk. We rationalize this behavior in terms of the geometric constraints imposed by the solute. These findings reverse the classical "iceberg" view of hydrophobic hydration by indicating that hydrophobic hydration water is less ice-like than bulk water. Our results also challenge the "structural temperature" concept. The two investigated osmolytes have opposite effects on protein stability but have virtually the same effect on water dynamics, suggesting that they do not act indirectly via solvent perturbations. The NMR-derived picture of hydrophobic hydration dynamics differs substantially from views emerging from recent quasielastic neutron scattering and pump-probe infrared spectroscopy studies of the same solutes. We discuss the possible reasons for these discrepancies.     

Invoking Pairwise Interactions in Water‐Promoted Diels–Alder Reactions by using Ionic Liquids as Cosolvents

Rate constants and derived activation parameters of organic reactions in aqueous media, in particular Diels–Alder reactions, are sensitive to the presence of cosolvents in water. To enhance the solubility window of water, we introduced ionic liquids as cosolvents in the aqueous Diels–Alder reaction between anthracene‐9‐carbinol and N‐ethylmaleimide. The reactive potentials of the organic compounds are parameterized by using semi‐empirical quantum chemical methods. The principle of Savage–Wood additivity of group interactions is used to quantify the pairwise group interactions among chemically inert ionic liquids and organic reactants, both at initial and transition states of the reaction. The present approach shows promise, as the use of simple calculations from easily available kinetic data can help researchers to understand the versatility of green ionic‐liquid alternatives to volatile organic solvents.     

Can the absence of solvation of neutral reagents by ionic liquids be responsible for the high reactivity in base-assisted intramolecular nucleophilic substitutions in these solvents?

[reaction: see text] The kinetics of the rearrangement of the Z-phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole (1a) into the relevant 4-benzoylamino-2,5-diphenyl-1,2,3-triazole (2a) induced by amines have been studied in two room-temperature ionic liquids (IL-1, [BMIM][BF4] and IL-2, [BMIM][PF6]). The data collected show that the reaction occurs faster in ionic liquids than in other conventional solvents previously studied (both polar or apolar, protic or aprotic). Presumably, this could depend on their peculiar ability to minimize the strong substrate-solvent, amine-solvent and amine-amine interactions occurring in conventional solvents.     

A new angle on heat capacity changes in hydrophobic solvation

The differential solubility of polar and apolar groups in water is important for the self-assembly of globular proteins, lipid membranes, nucleic acids, and other specific biological structures through hydrophobic and hydrophilic effects. The increase in water's heat capacity upon hydration of apolar compounds is one signature of the hydrophobic effect and differentiates it from the hydration of polar compounds, which cause a decrease in heat capacity. Water structuring around apolar and polar groups is an important factor in their differential solubility and heat capacity effects. Here, it is shown that joint radial/angular distribution functions of water obtained from simulations reveal quite different hydration structures around polar and apolar groups: polar and apolar groups have a deficit or excess, respectively, of "low angle hydrogen bonds". Low angle hydrogen bonds have a larger energy fluctuation than high angle bonds, and analysis of these differences provides a physical reason for the opposite changes in heat capacity and new insight into water structure around solutes and the hydrophobic effect.     

THE ROLE OF INTERFACIAL INTERACTIONS IN THE PARTICLE/BUBBLE ATTACHMENT

The Van Oss surface thermodynamic theory of polar and apolar interfacial interactions was extended to the interaction between mineral surfaces and bubbles across liquid media. The acid base (polar) interfacial interactions are supposed to be responsible for the hydration repulsion between a hydrophilic mineral and a bubble as well as for the hydrophobic attraction between a hydrophobic mineral and the bubble.     

Supramolecular polymers in aqueous medium: rational design based on directional hydrophobic interactions

Self-assembly in aqueous medium is of primary importance and widely employs hydrophobic interactions. Yet, unlike directional hydrogen bonds, hydrophobic interactions lack directionality, making difficult rational self-assembly design. Directional hydrophobic motif would significantly enhance rational design in aqueous self-assembly, yet general approaches to such interactions are currently lacking. Here, we show that pairwise directional hydrophobic/π-stacking interactions can be designed using well-defined sterics and supramolecular multivalency. Our system utilizes a hexasubstituted benzene scaffold decorated with 3 (compound 1) or 6 (compound 2) amphiphilc perylene diimides. It imposes a pairwise self-assembly mode, leading to well-defined supramolecular polymers in aqueous medium. the assemblies were characterized using cryogenic electron microscopy, small-angle X-ray scattering, optical spectroscopy, and EPR. Supramolecular polymerization studies in the case of 2 revealed association constants in 10(8) M(-1) range, and significant enthalpic contribution to the polymerization free energy. The pairwise PDI motif enables exciton confinement and localized emission in the polymers based on 1 and 2's unique photonic behavior, untypical of the extended π-stacked systems. Directional pairwise hydrophobic interactions introduce a novel strategy for rational design of noncovalent assemblies in aqueous medium, and bring about a unique photofunction.     

Enthalpy of hydrophobic hydration separately estimated for each -CH2-, -CF2-, and -OCH2CH2- unit component of amphiphiles and of related compounds

The enthalpy of hydrophobic hydration, DeltaH(HH), was separately estimated for each apolar segment of amphiphiles and of related compounds. The specimens analyzed in this study were the homologs and analogs of sodium alkyl sulfate, alkyltrimethylammonium bromide, ammonium perfluoroalkylcarboxylate, and polyethylene glycols. The DeltaH(HH) was calculated from the adiabatic compressibility beta of aqueous solution systematically measured for each homologs at varying concentrations and temperatures. Those data reported in the previous paper were utilized. The DeltaH(HH) estimated for each -CH(2)-, -CF(2)-, and -OCH(2)CH(2)- segments in both hydrophobic and hydrophilic parts of the amphiphiles was found to change depending on its locations in the molecule. The DeltaH(HH) for the first -CH(2)- unit which is adjacent to the head sulfate group of H(CH(2))(n)SO(4)Na was found to be negligibly small; however, it increases gradually as the position of the unit moves apart from the anionic head group and attains as large as -26.5 kcal/mol for the eighth -CH(2)-. The change of DeltaH(HH) of -CF(2)- unit in F(CF(2))(n)COONH(4) shows the similar tendency to H(CH(2))(n)SO(4)Na. The value of DeltaH(HH) is as small as -8 kcal/mol for the first -CF(2)-, however, it increases to -16 kcal/mol for the fifth -CF(2)-, which is 1.5 times larger than that of the fifth -CH(2)- of alkyl sulfate. Contrary to this, all the DeltaH(HH) of the methylenes of cationic surfactant ranging from the second to the eighth -CH(2)- units of H(CH(2))(n)N(CH(3))(3)Br take a similar value around -8 kcal/mol of -CH(2)- irrespective of their positions. The first -CH(2)- unit which is equivalent to that of quaternary ammonium [HCH(2)](4)NBr shows slightly higher value of -9.0 kcal/mol of the first -CH(2)- than those for the second to eighth -CH(2)-. This seems to suggest that the cationic core nitrogen has an enhancing effect on hydrophobic hydration. The hydration enthalpy DeltaH(OEH) of each oxyethylene (OE) unit of polyethylene glycol was also estimated for H(OCH(2)CH(2))(p)OH (p=1-4) homologues to see the roles of ether oxygen and hydroxyl groups in hydrophobic hydration. The value of DeltaH(OEH) showed its maximum -13.1 kcal/mol for the OE unit located at the middle of three. The other two units at both ends were found to take the value of -9.9 kcal/mol, smaller than that at the center. This could suggest that the hydrophobic hydration of the ethylene segment is largely enhanced by the neighboring ether oxygens.     

Interactions in aqueous nonelectrolyte systems. Gibbs energy of interaction of the ether group with the hydroxyl group and the amide group

Freezing temperatures of dilute aqueous solutions of equimolar mixtures of 1,3,5-trioxane with myo-inositol, d-mannitol, cyclohexanol, formamide, and acetamide, and 1,4-dioxane with myo-inositol, d-mannitol, formamide, and acetamide have been measured. These data yield pairwise Gibbs energies of interactions between the molecules in an aqueous solution. Using the group additivity principle, the results also yield the pairwise functional group Gibbs energies of interaction for the ether group with the hydroxyl and amide group. These results have been combined with all available data from the literature to yield the Gibbs energy and enthalpy of interaction of amides, ethers, alcohols, and saccharides in aqueous solution.To whom correspondence should be addressed.     

Effects of aqueous non-electrolytes on the compact coil → random coil conformational transition of poly(methacrylic acid)

The stability of the compact conformation of poly(methacrylic acid) (PMAA) in aqueous solution has been studied in the presence of a series of monohydric alcohols, urea and N-substituted ureas. All these additives reduced the rate retardation found for the neutral hydrolysis of 1-benzoyl-3-phenyl-1,2,4-triazole in aqueous solutions of unneutralized PMAA, most likely as the result of denaturation. The relative denaturing abilities of the additives were found to be governed by their relative hydrophobicities. Further support for the proposed denaturation of PMAA was found in results from potentiometric titrations, viscosity measurements and spectroscopic studies using the cationic dye ethidium bromide.     

Hydrophobicity and Reactivity of Base Hydrolysis of Some Novel Low Spin Fe(II) Amino Acid Schiff Base Complexes in Some Binary Aqueous Solvent Mixtures

Rate constants for base hydrolysis of bis(naphthylidene isoleucinate)iron (II) (nili), bis(naphthylidene leucinate)iron(II) (nli), bis(naphthylidene serinate)iron(II) (nsi), bis(salicylidene isoleucinate)iron(II) (sili), (salicylidene leucinate)iron(II) (sli), bis(salic- ylidene methioninate)iron(II) (smi), and (salicylidene tryptophanate)iron(II) (sti) have been reported in different binary aqueous mixtures at 298 K. The observed reactivity trends are discussed in terms of the hydrophilic and hydrophobic forms of the complexes investigated, as well as the transfer chemical potentials of hydroxide ion and the complex. Both the solvent–solute and solvent–solvent interactions have been considered. The hydrophobic character of the complexes studied was manifested by enhancing the rate of base hydrolysis at the initial addition of the different cosolvents; further addition led mostly to a decrease in reactivity, but, in some cases, the greater destabilization of OH^– ion by added DMSO and acetone increases the rate of base hydrolysis. The modified Savage–Wood equation, based on the principle of group additivity, was applied to estimate the observed kinetic medium effects.     

Substituent effects in synthetic lectins--exploring the role of CH-π interactions in carbohydrate recognition

Contacts between aromatic surfaces and saccharide CH groups are common motifs in natural carbohydrate recognition. These CH-π interactions are modeled in "synthetic lectins" which employ oligophenyl units as apolar surfaces. Here we report the synthesis and study of new synthetic lectins with fluoro- and hydroxy-substituted biphenyl units, designed to explore the role of π-electron density in carbohydrate CH-π interactions. We find evidence that recognition can be moderated through electronic effects but that other factors such as cavity hydration are also important and sometimes predominant in determining binding strengths.     

Freezing temperatures of aqueous solutions of methyl formate and ethyl acetate with a variety of nonelectrolytes. Gibbs energy of interaction of the ester group with other functional groups

Freezing temperatures of dilute aqueous solutions of ethyl acetate and mixtures with myo-inositol, D-mannitol, formamide, 1,3,5-trioxane, 1,4-dioxane, acetamide, hexamethylenetetramine, and methyl formate have been measured. In addition, freezing temperatures of dilute aqueous solutions of methyl formate and mixtures with the above solutes have been measured. From these data, the pairwise molecular Gibbs energies of interaction between the molecules were calculated. Using the additivity principle, the pairwise functional group Gibbs energies of interaction were calculated for ester group interactions with a variety of other functional groups.