Solvent Effects on

Solvent effects on Ipa values are also different for acids and bases. When acids ionize, two ions are generated for each neutral molecule that dissociates. This equilibrium is very sensitive to the dielectric constant of the medium. ThKpncreases markedly (the acid becomes weaker) in solvents of low dielectric constant. A shift of thehfe value of up to 2 pH units is not uncommon (Rubino, 1987). 

On the other hand, the ionization of bases is an isoelectronic process, and therefore the effect of solvent is much less usually th pdecreases slightly (the base becomes weaker). For this type 

In addition to considering an adjusted buffering range in mixed solvent systems, the effects of dilution on the pH of the formulation should also be considered (Rubino, 1987). As formulations containing mixed solvent systems are diluted, the solvent effects onWIievjil decrease. For example, the a of the buffer acid will decrease as the formulation is diluted due to the dilution of the cosolvent. The consequences of the pqbWnges on the physicochemical stability of the active compounds should be carefully studied. 

There are several well-established methods Iteg petermination (Albert and Serjeant, 1984). However, not all the methods are suitable for insoluble compounds. Sometimes, an estimation or prediction of the p might be sutcient depending on the need. Only some practical considerations pertinent to obtaining p values for insoluble compounds are discussed here. 

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PEP theory has also been applied to modelling the free energy profiles of reactions in solution. An important example is the solvent effect on the SN2 reaction... 

For analysing equilibrium solvent effects on reaction rates it is connnon to use the thennodynamic fomuilation of TST and to relate observed solvent-mduced changes in the rate coefficient to variations in Gibbs free-energy differences between solvated reactant and transition states with respect to some reference state. Starting from the simple one-dimensional expression for the TST rate coefficient of a unimolecular reaction a— r... 

If reliable quantum mechanical calcnlations of reactant and transition state stnictures in vacnnm are feasible, treating electrostatic solvent effects on the basis of SRCF-PCM rising cavity shapes derived from methods... 

Abraham M H 1974 Solvent effects on transition states and reaction rates Prog. Rhys. Org. Ohem. 11 1-87... 

Caste]on H and Wiberg K B 1999 Solvent effects on methyl transfer reactions. 1. The Menshutkin reaction J. Am. Ohem. Soc. 121 2139-46... 

Ladanyi B M and Hynes J T 1986 Transition state solvent effects on atom transfer rates in solution J. Am. Ohem. Soc. 108 585-93... 

Van der Zwan G and Hynes J T 1982 Dynamical polar solvent effects on solution reactions A simple continuum model J. Chem. Phys. 76 2993-3001... 

Cacace M G, Landau E M and Ramsden J J 1997 The Hofmeister series salt and solvent effects on interfacial phenomena Q. Rev. Biophys. 30 241-78... 

G. Ramachandran and T. Schlick. Solvent effects on supercoiled DNA dynamics explored by Langevin dynamics simulations. Phys. Rev. E, 51 6188-6203, 1995. 

The intensities are plotted vs. v, the final vibrational quantum number of the transition. The CSP results (which for this property are almost identical with CI-CSP) are compared with experimental results for h in a low-temperature Ar matrix. The agreement is excellent. Also shown is the comparison with gas-phase, isolated I. The solvent effect on the Raman intensities is clearly very large and qualitative. These show that CSP calculations for short timescales can be extremely useful, although for later times the method breaks down, and CTCSP should be used. 

Yun-Yu S, W Lu and W F van Gunsteren 1988. On the Approximation of Solvent Effects on Conformation and Dynamics of Cyclosporin A by Stochastic Dynamics Simulation Teclmiqi Molecular Simulation 1 369-383. 

Ha S, J Gao, B Tidor, J W Brady and M Karplus 1991. Solvent Effect on the Anomeric Equilibrium in d Glucose A Free Eneigy Simulation Analysis. Journal of the American Chemical Sod. ty 113 1553-1557... 

Solvents exert their influence on organic reactions through a complicated mixture of all possible types of noncovalent interactions. Chemists have tried to unravel this entanglement and, ideally, want to assess the relative importance of all interactions separately. In a typical approach, a property of a reaction (e.g. its rate or selectivity) is measured in a laige number of different solvents. All these solvents have unique characteristics, quantified by their physical properties (i.e. refractive index, dielectric constant) or empirical parameters (e.g. ET(30)-value, AN). Linear correlations between a reaction property and one or more of these solvent properties (Linear Free Energy Relationships - LFER) reveal which noncovalent interactions are of major importance. The major drawback of this approach lies in the fact that the solvent parameters are often not independent. Alternatively, theoretical models and computer simulations can provide valuable information. Both methods have been applied successfully in studies of the solvent effects on Diels-Alder reactions. 

Recently the solvent effect on the [4+2] cycloaddition of singlet oxygen to cyclic dienes has been subjected to a multiparameter analysis. A pre-equilibrium with charge-transfer character is involved, which is affected by the solvent through dipolarity-polarisability (n ) and solvophobic interactions ( Sjf and Another multiparameter analysis has been published by Gajewski, demonstrating the... 

The solvent effect on the diastereofacial selectivity in the reactions between cyclopentadiene and (lR,2S,5R)-mentyl acrylate is dominated by the hydrogen bond donor characteristics of the solvent... 

Unfortunately, the number of mechanistic studies in this field stands in no proportion to its versatility" . Thermodynamic analysis revealed that the beneficial effect of Lewis-acids on the rate of the Diels-Alder reaction can be primarily ascribed to a reduction of the enthalpy of activation ( AAH = 30-50 kJ/mole) leaving the activation entropy essentially unchanged (TAAS = 0-10 kJ/mol)" . Solvent effects on Lewis-acid catalysed Diels-Alder reactions have received very little attention. A change in solvent affects mainly the coordination step rather than the actual Diels-Alder reaction. Donating solvents severely impede catalysis . This observation justifies the widespread use of inert solvents such as dichloromethane and chloroform for synthetic applications of Lewis-acid catalysed Diels-Alder reactions. 

Studies on solvent effects on the endo-exo selectivity of Diels-Alder reactions have revealed the importance of hydrogen bonding interactions besides the already mentioned solvophobic interactions and polarity effects. Further evidence of the significance of the former interactions comes from computer simulations" and the analogy with Lewis-acid catalysis which is known to enhance dramatically the endo-exo selectivity (Section 1.2.4). 

Several alternative attempts have been made to quantify Lewis-acid Lewis-base interaction. In view of the HSAB theory, the applicability of a scale which describes Lewis acidity with only one parameter will be unavoidably restricted to a narrow range of struchirally related Lewis bases. The use of more than one parameter results in relationships with a more general validity ". However, a quantitative prediction of the gas-phase stabilities of Lewis-acid Lewis-base complexes is still difficult. Hence the interpretation, not to mention the prediction, of solvent effects on Lewis-add Lewis-base interactions remains largely speculative. 

Donor strengths, taken from ref. 207b, based upon the solvent effect on the symmetric stretching frequency of the soft Lewis acid HgBr2. Gutmann s donor number taken from ref 207b, based upon AHr for the process of coordination of an isolated solvent molecule to the moderately hard SbCL molecule in dichioroethane. ° Bulk donor number calculated as described in ref 209 from the solvent effect on the adsorption spectrum of VO(acac)2. Taken from ref 58, based on the NMR chemical shift of triethylphosphine oxide in the respective pure solvent. Taken from ref 61, based on the solvatochromic shift of a pyridinium-A-phenoxide betaine dye. 

The Dk parameter is based on the solvent effect, on the reaction of tetracyanoethylene with diazodiphenylmethane with benzene as a reference solvent. For details see Osbima, T. Arikata, S. Nagai, T. J. Chem. Research (S), 1981, 204... 

Table 2.4. Solvent effect on the Hammett p-values for the Diels-Alder reaction of2.4 with 2.5 catalysed by Cu(N03)2 at 25 - C.

Table 2,8, Solvent effect on the endo-exo selectivity (% endo -% exo) of the nncatalysed and Cu" -ion catalysed Diels-Alder reaction between 2,4c and 2,5 at 25°C.

Assuming London-dispersion and electrostatic interactions to be dominant in arene - arene interactions (see Section 3.2.7), the solvent effect on the enantioselectivify is anticipated to be influenced by the polarisability and polarity of the solvent. The arene -arene interaction is inferred to... 

Clearly, complete understanding of solvent effects on the enantioselectivity of Lewis-acid catalysed Diels-Alder reactions has to await future studies. For a more detailed mechanistic understanding of the origins of enantioselectivity, extension of the set of solvents as well as quantitative assessment of the strength of arene - arene interactions in these solvent will be of great help. 

The solvent effect on the rate constants of the Diels-Alder reaction of the ionic dienophiles If and Ig... 

An intramolecular charge transfer toward C-5 has been proposed (77) to rationalize the ultraviolet spectra observed for 2-amino-5-R-thiazoles where R is a strong electron attractor. Ultraviolet spectra of a series of 2-amino-4-p-R-phenylthiazoles (12) and 2-amino-5-p-R-phenylthiazoles (13) were recorded in alcoholic solution (73), but, reported in an article on pK studies, remained undiscussed. Solvent effects on absorption spectra of 2-acetamido and 2-aminothiazoles have been studied (92). 

A bathochromic shift of about 5 nm results for the 320-nm band when a methyl substituent is introduced either in the 4- or 5-posiiion, The reverse is observed when the methyl is attached to nitrogen (56). Solvent effects on this 320-nm band suggest that in the first excited state A-4-thiazoline-2-thione is less basic than in the ground state (61). Ultraviolet spectra of a large series of A-4-thiazoline-2-thiones have been reported (60. 73). 

TABLE VII-10a SOLVENT EFFECTS ON THE DIAZOMETHANE METHYLA-TION OF A-4-THIAZOLINE-2-THIONE AT 25°C ... 

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