New reaction simulator "LUMMOX" and its application for prediction of catalytic activities

We developed a new reaction simulator, "LUMMOX." It is an intermolecular interaction analyzer based on the theories of paired interacting orbitals (PIOs) and localized frontier orbitals (LFOs) that have been developed by Fujimoto et al. (Fukui, K.; Koga, N.; Fujimoto, H. J Am Chem Soc 1981, 103, 196; Fujimoto, H.; Koga, N.; Fukui, K. J Am Chem Soc 1981, 103, 7452; Fujimoto, H.; Satoh, S. J Phys Chem 1994, 98, 1436). LUMMOX runs on a Windows PC and displays graphic representation of orbital interactions. Prediction of activities, selectivities, and molecular weight of olefin polymerization catalysts are presented using PIO analysis and LFO calculation. Not only computational chemists but also experimental chemists can easily use this new system for catalyst design or molecular design from the point of view of orbital interaction.     

Determinants of cyanuric acid and melamine assembly in water

While the recognition of cyanuric acid (CA) by melamine (M) and their derivatives has been known to occur in both water and organic solvents for some time, analysis of CA/M assembly in water has not been reported (Ranganathan, A.; Pedireddi, V. R.; Rao, C. N. R. J. Am. Chem. Soc.1999, 121, 1752-1753; Mathias, J. P.; Simanek, E. E.; Seto, C. T.; Whitesides, G. M. Macromol. Symp.1994, 77, 157-166; Zerkowski, J. A.; MacDonald, J. C.; Seto, C. T.; Wierda, D. A.; Whitesides, G. M. J. Am. Chem. Soc.1994, 116, 2382-2391; Mathias, J. P.; Seto, C. T.; Whitesides, G. M. Polym. Prepr.1993, 34, 92-93; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc.1993, 115, 905-916; Zerkowski, J. A.; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc.1992, 114, 5473-5475; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc.1990, 112, 6409-6411; Wang, Y.; Wei, B.; Wang, Q. J. Chem. Cryst.1990, 20, 79-84; ten Cate, M. G. J.; Huskens, J.; Crego-Calama, M.; Reinhoudt, D. N. Chem.-Eur. J.2004, 10, 3632-3639). We have examined assembly of CA/M, as well as assembly of soluble trivalent CA and M derivatives (TCA/TM), in aqueous solvent, using a combination of solution phase NMR, isothermal titration and differential scanning calorimetry (ITC/DSC), cryo-transmission electron microscopy (cryo-TEM), and synthetic chemistry. While the parent heterocycles coprecipitate in water, the trivalent system displays more controlled and cooperative assembly that occurs at lower concentrations than the parent and yields a stable nanoparticle suspension. The assembly of both parent and trivalent systems is rigorously 1:1 and proceeds as an exothermic, proton-transfer coupled process in neutral pH water. Though CA and M are considered canonical hydrogen-bonding motifs in organic solvents, we find that their assembly in water is driven in large part by enthalpically favorable surface-area burial, similar to what is observed with nucleic acid recognition. There are currently few synthetic systems capable of robust molecular recognition in water that do not rely on native recognition motifs, possibly due to an incomplete understanding of recognition processes in water. This study establishes a detailed conceptual framework for considering CA/M heterocycle recognition in water which enables the future design of molecular recognition systems that function in water.     

Metastable isonitrosyl structure of the nitroprusside anion confirmed by nuclear inelastic scattering

Nuclear inelastic scattering (NIS) measurements were performed on a guanidium nitroprusside ((CN(3)H(6))(2)[Fe(CN)(5)NO], GNP) monocrystal at 77 K after the sample was illuminated with blue light (450 nm) at 50 K to populate the two metastable states, MS(1) and MS(2), of the nitroprusside anion. A second measurement was performed at 77 K after warming up the illuminated crystal to 250 K where the metastable states decay to the groundstate. The measured spectra were compared with simulated NIS spectra that were calculated by using density functional methods. Comparison of measured and simulated spectra provides strong evidence for the isonitrosyl structure of the metastable MS(1) state proposed by Carducci et al. (Carducci, M. D.; Pressprich, M. R.; Coppens, P. J. Am. Chem. Soc. 1997, 119, 2669-2678).     

Conserved mechanism of copper binding and transfer. A comparison of the copper-resistance proteins PcoC from Escherichia coli and CopC from Pseudomonas syringae

The copper-resistance proteins PcoC from Escherichia coli and CopC from Pseudomonas syringae exhibit 67% sequence identity, but the chemistry reported for PcoC (Peariso, K.; Huffman, D. L.; Penner-Hahn, J. E.; O'Halloran, T. V. J. Am. Chem. Soc. 2003, 125, 342-343) was distinctly different from that reported for CopC (Zhang, L.; Koay, M.; Maher, M. J.; Xiao, Z.; Wedd, A. G. J. Am. Chem. Soc. 2006, 128, 5834-5850). The source of the inconsistency has been identified, and His1 is confirmed as an unprecedented bidentate ligand in each protein. Access to a bona fide wild-type PcoC protein allowed unequivocal observation of intermediates involved in intermolecular redox copper transfer reactions.     

Do spin state changes matter in organometallic chemistry? A computational study

Spin changes occur often in organometallic chemistry, and their effect on kinetics is not well understood. We report computations on the singlet and triplet potential energy surfaces of several processes of this type and show that the topology of the individual surfaces, as well as of the crossing regions between them, can be used to rationalize the observed reactivity in all cases. In particular, the slow addition of dihydrogen to W[N(CH(2)CH(2)NSiMe(3))(3)]H (Schrock, R. R.; Shih, K. Y.; Dobbs, D. A.; Davis, W. M. J. Am. Chem. Soc. 1995, 117, 6609) is shown to be a "spin-blocked" reaction with a high barrier due to the crossing between reactant triplet and product singlet surfaces. In contrast, addition of CO to TpCo(CO) (Detrich, J. L.; Reinaud, O. M.; Rheingold, A. L.; Theopold, K. H. J. Am. Chem. Soc. 1995, 117, 11745) is fast because the triplet and singlet surfaces cross at low energy. Particular care is taken to use DFT methods which are in adequate agreement with experimental and high-level computational energetics for these systems.     

Linear NiII-MnIII2-NiII tetramers: an oligomeric component of the MnIII2NiII single-chain magnets

Heterometallic linear tetramers [Mn(5-R-saltmen)Ni(pao)(bpy)(2)](2)(ClO(4))(4) (5-R-saltmen(2-) = N,N'-1,1,2,2-tetramethylethylene bis(5-R-salicylideneiminate); pao(-) = pyridine-2-aldoximate; bpy = 2,2'-bipyridine, R = H, 1; Cl, 2; Br, 3; MeO, 4) have been synthesized and structurally characterized. These compounds exhibit a [Ni(II)-NO-Mn(III)-(O)(2)-Mn(III)-ON-Ni(II)] skeleton where -ON- is an oximate bridge between Mn(III) and Ni(II) ions and -(O)(2)- is a bi-phenolate bridge between Mn(III) ions. These tetramers can be seen as oligomeric units of the heterometallic Mn(III)(2)-Ni(II) chain observed in a family of single-chain magnets (Clérac, R.; Miyasaka, H.; Yamashita, M.; Coulon, C. J. Am. Chem. Soc. 2002, 124, 12837. Miyasaka, H.; Clérac, R.; Mizushima, K.; Sugiura, K.; Yamashita, M.; Wernsdorfer, W.; Coulon, C. Inorg. Chem. 2003, 42, 8203.). Magnetic measurements on these tetramers confirm the nature of the magnetic interactions reported for the Mn(III)(2)-Ni(II) chains: a strong antiferromagnetic Mn(III)/Ni(II) coupling via the oximate bridge (J(Ni-Mn) ranges from -23.7 to -26.1 K) and a weak ferromagnetic Mn(III)/Mn(III) coupling through the bi-phenolate bridge (J(Mn-Mn) ranges from +0.4 to +0.9 K). These magnetic interactions lead to tetramers with an S = 2 ground state.     

Radical clock substrates, their C-H hydroxylation mechanism by cytochrome P450, and other reactivity patterns: what does theory reveal about the clocks' behavior?

There is an ongoing and tantalizing controversy regarding the mechanism of a key process in nature, C-H hydroxylation, by the enzyme cytochrome P450 (Auclaire, K.; Hu, Z.; Little, D. M.; Ortiz de Montellano, P. R.; Groves, J. T. J. Am. Chem. Soc. 2002, 124, 6020-6027. Newcomb, M.; Aebisher, D.; Shen, R.; Esala, R.; Chandrasena, P.; Hollenberg, P. F.; Coon, M. J. J. Am. Chem. Soc. 2003, 125, 6064-6065). To definitely resolve this controversy, theory must first address the actual systems that have been used by experiment, and that generated the controversy. This is done in the present paper, which constitutes the first extensive theoretical study of such two experimental systems, trans-2-phenylmethyl-cyclopropane (1) and trans-2-phenyl-iso-propylcyclopropane (4). The theoretical study of these substrates reveals that the only low energy pathway for C-H hydroxylation is the two-state rebound mechanism described originally for methane hydroxylation (Ogliaro, F.; Harris, N.; Cohen, S.; Filatov, M.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000, 122, 8977-8989). The paper shows that the scenario of a two-state rebound mechanism accommodates much of the experimental data. The computational results provide a good match to experimental results concerning the very different extents of rearrangement for 1 (20-30%) vs 4 (virtually none), lead to product isotope effect for the reaction of 1, in the direction of the experimental result, and predict as well the observed metabolic switching from methyl to phenyl hydroxylation, which occurs upon deuteration of the methyl group. Furthermore, the study reveals that an intimate ion pair species involving an alkyl carbocation derived from 4 gives no rearranged products, again in accord with experiment. This coherent match between theory and experiment cannot be merely accidental; it comes close to being aproof that the actual mechanism of C-H hydroxylation involves the two-state reactivity revealed by theory. Analysis of the rearrangement modes of the carbocations derived from 1 and 4 excludes the participation of free carbocations during the hydroxylation of these substrates. Finally, the mechanistic significance of product isotope effect (different isotope effects for the rearranged and unrearranged alcohol products) is analyzed. It is shown to be a sensitive probe of two-state reactivity; the size of the intrinsic product isotope effect and its direction reveal the structural differences of the hydrogen abstraction transition states in the low-spin vs high-spin reaction manifolds.     

Tension-induced morphological transition in mixed lipid bilayers

Recently, Rozovsky et al. reported on the morphology and dynamics of superstructures in three-component lipid bilayers containing saturated lipid, unsaturated lipid, and cholesterol (Rozovsky, S.; Kaizuka, Y.; Groves, J. T. J. Am. Chem. Soc. 2005, 127, 36). We suggest that the observed sequence of the striped-to-hexagonal morphological transition in mixed bilayers can be attributed to an enhanced membrane surface tension that is induced by the vesicle adhesion onto the solid surface.     

Origin of the nonplanarity of tetrafluoro cyclobutadiene, C4F4

Density functional theory as well as M?ller-Plesset investigations has been carried out on tetrafluoro cyclobutadiene, C4F4, to explore the origin of its nonplanarity. Although Petersson et al. (Petersson, E. J.; Fanuele, J. C.; Nimlos, M. R.; Lemal, D. M.; Ellison, G. B.; Radziszewski, J. G. J. Am. Chem. Soc. 1997, 119, 11122-11123) had earlier predicted a nonplanar geometry of this compound on the basis of spectral and bond orbital analysis, the explanation of the same from a more fundamental point of view is still missing. In the present study, we provide a heuristic explanation for the origin of nonplanarity of C4F4. The two major driving forces behind this nonplanar geometry are the unusual aromaticity of this cyclic homoatomic 4pi electron system and the second-order Jahn-Teller effect (SOJTE). These driving forces can well be explained by various energy and density parameters and also by nucleus-independent chemical shift (NICS) values. Aromaticity of a cyclic homoatomic 4pi electron system is quite remarkable. The enhancement of pi- delocalization as evidenced from molecular orbital analysis may be attributed to s-ppi mixing in nonplanar C4F4.     

55Mn pulse ENDOR at 34 GHz of the S0 and S2 states of the oxygen-evolving complex in photosystem II

55Mn pulse ENDOR experiments at 34 GHz (Q-band) are reported for the S0 and S2 states of the oxygen-evolving complex of photosystem II. Their numerical analysis (i) shows that in both states all four Mn ions are magnetically coupled, (ii) allows a refinement of the hyperfine interaction (HFI) parameters obtained earlier for the S2 state at X-band (Peloquin, J. M.; Campbell, K. A.; Randall, D. W.; Evanchik, M. A.; Pecoraro, V. L.; Armstrong, W. H.; Britt, R. D. J. Am. Chem. Soc. 2000, 122, 10926-10942), (iii) provides the first reliable 55Mn HFI tensors for the S0 state, and (iv) leads to the suggestion that the Mn oxidation states in S0 and S2 are Mn4(III, III, III, IV) and Mn4(III, IV, IV, IV), respectively. In addition, a Q-band EPR spectrum is reported for the S0 state, and inversion-recovery experiments at 4.5 K directly show that the electron spin-lattice relaxation for the S0 state is about 2 orders of magnitude faster than that for the S2 state.     

Metal ion binding by a bicyclic diamide: deep UV Raman spectroscopic characterization

Deep UV resonance Raman spectroscopy was used for characterizing ligand-metal ion complexes. The obtained results demonstrated a strong intrinsic sensitivity and selectivity of a Raman spectroscopic signature of a bicyclic diamide, a novel chelating agent for lanthanides and actinides (Lumetta, G. J.; Rapko, B. M.; Garza, P. A.; Hay, B. P.; Gilbertson, R. D.; Weakley, T. J. R.; Hutchison, J. E. J. Am. Chem. Soc. 2002, 124, 5644). Molecular modeling, which included structure optimization and calculation of Raman frequencies and resonance intensities, allowed for assigning all strong Raman bands of the bicyclic diamide as well as predicting the band shifts observed because of complex formation with metal ions. A comparative analysis of Raman spectra and the results of the molecular modeling could be used for elucidating the structure of complexes in solution.     

The effect of heme environment on the hydrogen abstraction reaction of camphor in P450cam catalysis: a QM/MM study

The discrepancies between the published QM/MM studies (Sch?neboom, J. C.; Cohen, S.; Lin, H.; Shaik, S.; Thiel, W. J. Am. Chem. Soc. 2004, 126, 4017; Guallar, V.; Friesner, R. A. J. Am. Chem. Soc. 2004, 126, 8501) on H-abstraction of camphor in P450cam have largely been resolved. The crystallographic water molecule 903 situated near the oxo atom of Compound I acts as a catalyst for H-abstraction, lowering the barrier by about 4 kcal/mol. Spin density at the A-propionate side chain of heme can occur in the case of incomplete screening but has no major effect on the computed barrier.     

Structural studies of nonclassical cyclobutylmethyl cations by the ab initio method

Ab initio calculations at the MP2/cc-pVTZ level show that the cyclobutylmethyl cation is a nonclassical sigma-delocalized species, which is distinct from the global minimum C2-symmetric cyclopentyl cation (Schleyer, P. v. R.; Carneiro, J. W. de M.; Koch, W.; Raghavachari, K. J. Am. Chem. Soc. 1989, 111, 5475). Relatively lower level DFT calculations, on the other hand, show that the primary cyclobutylmethyl cation spontaneously collapses into the cyclopentyl cation (Prakash, G. K. S.; Reddy, V. P.; Rasul, G.; Casanova, J.; Olah, G. A. J. Am. Chem. Soc. 1998, 120, 13362). The secondary 1-cyclobutylethyl cation is also a nonclassical carbocation, as shown by calculations at the MP2/cc-pVTZ level. Two structures having energy minima are identified for the latter cation on the potential energy surface. The conformer in which the methyl group is in the exo orientation is a global minimum and is favored over the corresponding endo conformer by 1.2 kcal/mol at the MP2/cc-pVTZ//MP2/cc-pVTZ +ZPE level of calculations. The tertiary 1-cyclobutyl-1-methylethyl cation, at this level of calculations, also involves substantial nonclassical sigma-delocalization, showing that the nonclassical stabilization is more important for cyclobutylmethyl cations relative to the cyclopropylmethyl cations. The 13C NMR chemical shifts obtained from GIAO-CCSD(T)/tzp/dz calculations further substantiate the nonclassical structures for these carbocations.     

Nickel complexes of a bulky beta-diketiminate ligand

Nickel(II) chloride forms a complex with tetrahydrofuran, NiCl(2)(THF)(1.5), that can be used to prepare nickel chloride complexes of a bulky beta-diketiminate ligand L(Me). [L(Me)NiCl](2) and L(Me)NiCl(2)LiTHF(2), which have tetrahedral geometries in the solid state, are in equilibrium with three-coordinate L(Me)NiCl. Thermodynamic parameters for the equilibrium between [L(Me)NiCl](2) and L(Me)NiCl are DeltaH = 51(5) kJ/mol and DeltaS = 116(11) J/(mol.K). L(Me)NiCl forms a tetrahydrofuran complex with a binding constant of 1.2(2) M(-)(1) at 21 degrees C. The chloride complexes were used to generate a three-coordinate nickel(II)-amido complex. This amido complex, L(Me)NiN(SiMe(3))(2), is compared with L(Me)MN(SiMe(3))(2) (M = Mn, Fe, Co) (Panda, A.; Stender, M.; Wright, R. J.; Olmstead, M. M.; Klavins, P.; Power, P. P. Inorg. Chem. 2002, 41, 3909-3916). Trends in the metrical parameters of the three-coordinate L(Me)M(II) amido compounds are similar to the trends in three-coordinate L(tBu)M(II) chloride compounds (Holland, P. L.; Cundari, T. R.; Perez, L. L.; Eckert, N. A.; Lachicotte, R. J. J. Am. Chem. Soc. 2002, 124, 14416-14424).     

Synthesis and properties of a fluorene-capped isotruxene: a new unsymmetrical star-shaped pi-system

An unsymmetrical star-shaped pi-system (1) with an isotruxene core and three fluorene arms has been synthesized, and its photophysical, electrochemical, and thermochemical properties have been investigated and compared with the corresponding symmetrical truxene derivatives 2a-d (Kanibolotsky, A. L.; Berridge, R.; Skabara, P. J.; Perepichka, I. F.; Bradley, D. D. C.; Koeberg, M. J. Am. Chem. Soc. 2004, 126, 13695-13702). Stronger electronic couplings between the arms in 1 vs 2a-d lead to lower optical band gap, larger splitting in oxidation potentials, and superior thermostability. [structure: see text]     

The phenylnitrene rearrangement in the inner phase of a hemicarcerand

The photochemistry of phenyl azide 1 and 13C-labeled phenyl azide 13C-1 incarcerated inside a hemicarcerand 4 was investigated. Low-temperature photolysis of hemicarceplex 41 and 413C-1 yields incarcerated 1-azacyclohepta-1,2,4,6-tetraene 42 and 413C-2 (18-50%), respectively, which were characterized by low-temperature FT-IR and 1H NMR and 13C NMR spectroscopy. After correction for the hemicarcerand-induced upfield shift, the 13C chemical shifts of incarcerated 13C-2 compare very well (Deltadelta 相似文献   

The high-valent iron-oxo species of polyoxometalate, if it can be made, will be a highly potent catalyst for C-H hydroxylation and double-bond epoxidation

This study uses density functional theory (DFT) calculations to explore the reactivity of the putative high-valent iron-oxo reagent of the iron-substituted polyoxometalate (POM-FeO4-), derived from the Keggin species, PW12O40(3-). It is shown that POM-FeO4- is in principle capable of C-H hydroxylation and C=C epoxidation and that it should be a powerful oxidant, even more so than the Compound I species of cytochrome P450. The calculations indicate that in a solvent, the barriers, and especially those for epoxidation, become sufficiently small that one may expect an extremely fast reaction. An experimental investigation (by R.N. and A.M.K.) shows, however, that the formation of POM-FeO4- using the oxygen donor, F5PhI-O, leads to a persistent adduct, POM-FeO-I-PhF5(4-), which does not decompose to POM-FeO4- + F5Ph-I at the working temperature and exhibits sluggish reactivity, in accord with previous experimental results (Hill, C. L.; Brown, R. B., Jr. J. Am. Chem. Soc. 1986, 108, 536 and Mansuy, D.; Bartoli, J.-F.; Battioni, P.; Lyon, D. K.; Finke, R. G. J. Am. Chem. Soc. 1991, 113, 7222). Subsequent calculations indeed reveal that the gas-phase binding energy of F5PhI to POM-FeO4- is high (ca. 20 kcal/mol) compared to the corresponding binding energy of propene (ca. 2-3 kcal/mol). As such, the POM-FeO-I-PhF5(4-) complex is expected to be persistent toward the displacement of F5PhI by a substrate like propene, leading thereby to sluggish oxidative reactivity. According to theory, overcoming this technical difficulty may turn out to be very rewarding. The question is, can POM-FeO4- be made?     

Proton-coupled electron transfer from tryptophan: a concerted mechanism with water as proton acceptor

The mechanism of proton-coupled electron transfer (PCET) from tyrosine in enzymes and synthetic model complexes is under intense discussion, in particular the pH dependence of the PCET rate with water as proton acceptor. Here we report on the intramolecular oxidation kinetics of tryptophan derivatives linked to [Ru(bpy)(3)](2+) units with water as proton acceptor, using laser flash-quench methods. It is shown that tryptophan oxidation can proceed not only via a stepwise electron-proton transfer (ETPT) mechanism that naturally shows a pH-independent rate, but also via another mechanism with a pH-dependent rate and higher kinetic isotope effect that is assigned to concerted electron-proton transfer (CEP). This is in contrast to current theoretical models, which predict that CEP from tryptophan with water as proton acceptor can never compete with ETPT because of the energetically unfavorable PT part (pK(a)(Trp(?)H(+)) = 4.7 ? pK(a)(H(3)O(+)) ≈ -1.5). The moderate pH dependence we observe for CEP cannot be explained by first-order reactions with OH(-) or the buffers and is similar to what has been demonstrated for intramolecular PCET in [Ru(bpy)(3)](3+)-tyrosine complexes (Sjo?din, M.; et al. J. Am. Chem. Soc.2000, 122, 3932. Irebo, T.; et al. J. Am. Chem. Soc.2007, 129, 15462). Our results suggest that CEP with water as the proton acceptor proves a general feature of amino acid oxidation, and provide further experimental support for understanding of the PCET process in detail.     

Enthalpy-entropy contributions to salt and osmolyte effects on molecular-scale hydrophobic hydration and interactions

Salts and additives can significantly affect the strength of water-mediated interactions in solution. We present results from molecular dynamics simulations focused on the thermodynamics of hydrophobic hydration, association, and the folding-unfolding of a hydrophobic polymer in water and in aqueous solutions of NaCl and of an osmolyte trimethylamine oxide (TMAO). It is known that addition of NaCl makes the hydration of hydrophobic solutes unfavorable and, correspondingly, strengthens their association at the pair as well as the many-body level (Ghosh, T.; Kalra, A.; Garde, S. J. Phys. Chem. B 2005, 109, 642), whereas the osmolyte TMAO has an almost negligible effect on the hydrophobic hydration and association (Athawale, M. V.; Dordick, J. S.; Garde, S. Biophys. J. 2005, 89, 858). Whether these effects are enthalpic or entropic in origin is not fully known. Here we perform temperature-dependent simulations to resolve the free energy into entropy and enthalpy contributions. We find that in TMAO solutions, there is an almost precise entropy-enthalpy compensation leading to the negligible effect of TMAO on hydrophobic phenomena. In contrast, in NaCl solutions, changes in enthalpy dominate, making the salt-induced strengthening of hydrophobic interactions enthalpic in origin. The resolution of total enthalpy into solute-solvent and solvent-solvent terms further shows that enthalpy changes originate primarily from solvent-solvent energy terms. Our results are consistent with experimental data on the hydration of small hydrophobic solutes by Ben-Naim and Yaacobi (Ben-Naim, A.; Yaacobi, M. J. Phys. Chem. 1974, 78, 170). In combination with recent work by Zangi, Hagen, and Berne (Zangi, R.; Hagen, M.; Berne, B. J. J. Am. Chem. Soc. 2007, 129, 4678) and the experimental data on surface tensions of salt solutions by Matubayasi et al. (Matubayasi, N.; Matsuo, H.; Yamamoto, K.; Yamaguchi, S.; Matuzawa, A. J. Colloid Interface Sci. 1999, 209, 398), our results highlight interesting length scale dependences of salt effects on hydrophobic phenomena. Although NaCl strengthens hydrophobic interactions at both small and large length scales, that effect is enthalpy-dominated at small length scales and entropy-dominated for large solutes and interfaces. Our results have implications for understanding of additive effects on water-mediated interactions, as well as on biocompatibility of osmolyte molecules in aqueous solutions.