We attempt to analyze whether experimental entropies, enthalpies and f
ree energies of hydration of small uncharged molecules can be quantita
tively rationalized with a continuum model including a classical react
ion field formalism. We find that a simple proportionality to accessib
le surface with five different atom types allows satisfactory (within
1-1.5 kcal/mol) reproduction of hydration entropies (T Delta S) of ove
r 40 solutes. The agreement with experiment can possibly be improved i
f proximity effects and configurational contributions to transfer entr
opies are taken into account. In calculations of hydration enthalpies
a reasonable agreement with experimental data can be obtained only whe
n solute polarizability is taken into account. Electrostatic contribut
ions to calculated hydration enthalpies exhibit strong dependencies on
both the magnitude and the direction of molecular dipole moments. We
demonstrate that for 20 molecules with experimentally measured vacuum
dipole moments density functional calculations with DZVPD basis set in
cluding diffuse functions on d-orbitals allows prediction of experimen
tal dipole moments within 0.1 D. At a fixed direction of the molecular
dipole moment, mu, the electrostatic component of hydration enthalpy
varies as mu(2). Thus an uncertainty of 0.1 D corresponds to uncertain
ties of 0.5-0.7 kcal/mol in hydration enthalpies of most small dipolar
solutes. A 30 degrees change in the direction of the molecular dipole
together with the corresponding change in the quadrupole moment can r
esult in a change of hydration enthalpy of 3 kcal/mol. Changes in the
quadrupole moment alone can result in hydration enthalpy changes of ov
er 1 kcal/mol. Representations of multipole expansions by point charge
s on nuclei fitted to molecular electrostatic potentials cannot accura
tely reproduce all these factors. Use of such point charges in calcula
tions of hydration enthalpies predictably leads to discrepancies with
experiment of approximate to 3 kcal/mol for some solutes. However, err
ors in hydration enthalpies and hydration entropies are usually compen
sating leading in most cases to agreement between calculated and exper
imental free energies of hydration within 1.5 kcal/mol.