Theory of the hydrophobic effect

Lawrence R. Pratt and David Chandler

Citation: The Journal of Chemical Physics 67, 3683 (1977); doi: 10.1063/1.435308
View online: http://dx.doi.org/10.1063/1.435308
View Table of Contents: http://aip.scitation.org/toc/jcp/67/8
Published by the American Institute of Physics

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Theory of the hydrophobic effect a)
Lawrence R. Pratt b) and David Chandler
School of Chemical Sciences, University of Illinois, Urbana, Illinois 61801
(Received 15 June 1977)

A microscopic theory is developed which can describe many of the structural and thermodynamic
properties of infinitely dilute solutions of apolar solutes in liquid water. The theory is based on an integral
equation for the pair correlation functions associated with spherical apolar species dissolved in water. It
requires as input the experimentally determined oxygen--{)xygen correlation function for pure liquid water.
The theory is tested by computing thermodynamic properties for aqueous solutions of apolar solute species.
The predictions of both the Henry's Law constant and the entropy of solution are in good agreement with
experiment. The calculation of the latter quantity is essentially independent of any adjustable parameters.
It is shown how the correlation functions we have calculated can be used to predict the solubility of more
complicated, aspherical, and nonrigid solutes in liquid water. For the more complex molecules it is
convenient to study the difference between the excess chemical potential of the molecule and the chemical
potentials of its separated components (Ben-Naim's measure of the hydrophobic interaction strength
oA ~I). A generalized formula for oA Z/I) is presented which reduces to Ben-Nairn's result in the special
case of a rigid solute. The calculations of oA Z/I) for normal alkanes through n-decane are independent of
unknown and adjustable mean field parameters. For ethane. the theoretical results for oA Z/I) are in good
agreement with experimental data. To treat longer alkanes multipoint correlation functions are required.
It is shown that the standard superposition approximation for the multipoint correlation functions predicts
qualitatively incorrect results. A correction to the superposition approximation is developed. Its use yields
theoretical values for oA Z/I) which agree well with experiment. We also calculate free energies of transfer
of n -alkane solutes from a hydrocarbon solvent to liquid water. Here, too, our results are in good
agreement with experiment. After testing the theory against experiment, several experimentally
inaccessible aspects of the hydrophobic effect are discussed. Analysis of pair correlation functions between
spherical apolar species indicates that the hydrophobic interaction becomes more attractive as the solute
size is increased at constant temperature, or as the temperature is decreased. The solute-solute
correlations in liquid water are compared with those in a nonassociated (hard-spherelike) solvent. Plots are
presented which indicate that the insertion of an apolar species increases the intermolecular structure of
water in the vicinity of the apolar solute. The effects of solvent environments on the conformations of
small chain molecules are discussed. It is shown that hydrocarbon solvents as well as water tend to reduce
the spatial extension of the chain molecules from what is found in the gas phase. However, calculations
which take cognizance of the detailed structure of the solvent liquids reveal that the average
conformational structure of some n -alkanes may be more compact in some non associated solvents than in
water.

I. INTRODUCTION apolar species is a semiempirical one. In particular,

Traditional descriptions of the stability of biologically
important macromolecular structures l -6 have relied on
the concept of a hydrophobic interaction which represents
some sort of effective attraction between apolar com-
ponents of these structures. This effective attraction
has been thought to be a result of the peculiar structure
of liquid water. Therefore, much effort has been in-
vested in studies of dilute solutions of apolar solutes
in liquid water, 7-13
a theoretical scheme is employed which expresses
solute pair correlations in terms of correlation func-
tions for the pure liquid water solvent. The oxygen-
oxygen pair correlations for pure water are known to
great accuracy at one atmosphere pressure between
a and 100 aC. 14 Our theory uses these experimentally
determined functions. We do not attempt to solve the
problems associated with the development of an ab
initio theory of liquid water.

In this paper we report calculations of the structural
and thermodynamic properties of dilute solutions of
apolar molecules in liquid water. Because the present
calculations derive from microscopically well-defined
approximations and yield structural properties, as well
as thermodynamic properties, we feel that the results
can clarify many of the ambiguities concerning micro-
scopic interpretation of hydrophobic phenomena.
Our strategy for calculating correlations between
alThis research has been supported by a grant from the Nation-
al Science Foundation and by a grant from the Petroleum Re-
search Fund, administered by the American Chemical Society.
blAddress after September 1977: Department of Chemistry,
Harvard University, Cambridge, MA 02138.
There are two aspects of the liquid water problem
which motivates a semiempirical approach in studying
properties associated with apolar solutes. First, our
knowledge of the interaction potentials between water
molecules is perhaps too primitive to hope that the be-
havior of real water in the vicinity of an apolar species
can be accurately represented by the behavior of a
model for water. Narten and Levy's measurements14
reveal a very large temperature dependence in the in-
termolecular structure of liquid water. This large tem-
perature dependence, which gives rise to the unusually
high value for the constant volume heat capacity, 15 im-
plies a great sensitivity to details in the intermolecular
potential. If small changes in temperature produce
large changes in structure, then necessarily small al-
terations in the intermolecular potentials can also be

The Journal of Chemical Physics, Vol. 67, No.8, 15 October 1977 Copyright 1977 American Institute of Physics 3683
3684 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
significant. Thus, it seems desirable to avoid making
unnecessary errors by not adopting an intermolecular
potential model for water.
The second motivation for a semiempirical approach
is the apparent unavailability of any simple microscopic
theory for the structure of fluids with strong attractive
interactions. The current state of the art allows us
to study the effects of strong repulsive interactions and
weak attractive intermolecular forces. For most
liquids these are the only kinds of interactions. But
water molecules interact with strong attractive "hy-
drogen bonds" that can actually compete with the re-
pulsions even at liquid densities. This competition is
unusual. It is found in few other one component liquids.
At liquid densities molecules are so close together that
typical attractions are swamped by the large short-
ranged repulsions, and the repulsions dominate the
structure for most liquids. But the viability of com-
petition between attractions and repulsions in water
makes this liquid behave in unusual ways. To do justice
to the microscopic properties of aqueous solutions, an
acceptable theory must describe this competition. There
seems to be two ways to do it. Either a theory must be
employed that can handle the statistical mechanics of
hydrogen bonds, or else a semiempirical procedure
must be used which inserts the experimental behavior
of real water. Since we do not have a simple answer to
the statistical mechanical problems, the second alterna-
tive seems to be the more practical approach.
We are not. of course, the first workers to develop
a semiempirical theory for dilute aqueous solutions of
apolar solute species. Pierotti 8 and Stillinger 13 have
both devised scaled particle theories 16 for such systems
that use pure water properties as input. However,
neither of these efforts attempted to calculate the pair
correlation functions associated with the solute species.
It is in this crucial regard that the research reported in
this article is distinguished from earlier work.
In order to investigate both the water structure in the
vicinity of an apolar species and the correlations be-
tween two solute molecules one calculates, approxi-
mately, the changes in the densities of solvent molecules
and solute molecules at r due to the introduction of a
solute molecule at the origin. The response of the den-
sities, of cburse, is strongly dependent on the struc-
ture of the host fluid in the absence of the disturbance. As
a result the equations we obtain when an apolar species
is fixed at the origin depend on the water-water corre-
lation functions for pure water. The approximations
made when employing this procedure are motivated by
empirical experience with integral equations in the
theory of the liquid state. The phySical approximations
which we adopt can also be used to derive the percus-
yevick integral equation17 for the hard sphere liquid,
and the RISM integral equation18 for hard core but
aspherical models of molecular liquids. Both the Per-
cus-Yevick and RISM theories have been relatively
successful in describing correlations between species
which interact through harshly repulsive forces. In
the present semiempirical approach we describe only
the effects of repulsive interactions. The quickly vary-
J. Chem. Phys., Vol. 67, No.8, 15 October 1977
ing attractive forces between water molecules are in-
corporated by using the exact experimentally deter-
mined water-water correlation function. Since our
method for treating repulsive interactions has been
shown to be accurate in a wide variety of applications,
it seems likely that our integral equation should provide
a qualitatively correct description of the correlations of
apolar solutes with water molecules and with other sol-
ute molecules.
The development of the theory in Sec. II is divided
into several parts. In Part A notational conventions are
established. Our microscopic interaction model for
apolar molecules in water is defined in PartB along with
some essential ideas of modern liquid state perturba-
tion theory. 19-22 Part C contains the derivation of our
theory for pair correlations. Finally, in Part D we dis-
cuss how the pair correlations can be used to investi-
gate conformational structures and thermodynamic
properties of nonspherical solute species such as nor-
mal alkanes.
The theory is tested against experimental measure-
ments of thermodynamic properties in Sec. III. Unless
great care is taken such properties depend sensitively
upon mean field terms that involve unknown (and thus
adjustable) parameters. These parameters have nothing
to do with intermolecular structure. However, as Ben-
Naim has observed,10 some measured thermodynamic
properties can be combined to yield properties that de-
pend primarily upon structural properties-both intra-
molecular conformations and intermolecular correla-
tions. Our calculations in Sec. III focus attention on
these properties, and we are able to accurately pre-
dict them with no adjustable parameters.
As we have previously emphasized, our theory repre-
sents an advance over previous theories primarily in
that it provides a detailed microscopic view of the local
structure of a dilute solution of apolar molecules in
liquid water. By comparison with available thermody-
namic data we have concluded that the theory is quali-
tatively accurate. However, several of the theoretical
predictions regarding the nature of the microscopic
structure of the fluid near an apolar solute have not and
perhaps cannot be probed directly by experiment. In
Sec. IV we discuss these predictions. Section V pro-
vides a summary of the Significant conclusions which
may be drawn from this work.
In closing this Introduction, it is worth stressing that
all the experimental properties which we use as a test
of our theory are those associated with hydrophobic
hydration and the deviations of hydrophobic hydration
from group additivity. Another class of effects are as-
sociated with the hydrophobic interaction or bond. This
second group is undoubtedly important in explaining
various biological phenomena. Our theory addresses
both types-hydrophobic hydration and hydrophobic in-
teractions. The two classes of hydrophobic effects are
different. They should not be confused with one another.
We believe the hydration phenomena are important be-
cause they can be used to test a microscopic theory.
If the theory is successful, it can then be used to eluci-
 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
date the experimentally inaccessible hydrophobic bond-
ing.
II. THEORY
A. Pair correlation functions
The equilibrium pair distribution function plfJ,(1 M,
2M') is defined as the joint probability distribution for
finding a molecule of type M with coordinates 1M and
another molecule of type M' with coordinates 2M" If
the molecules under consideration are not spherical,
the coordinate labels 1M and 2M' must be of high dimen-
sionality. A simpler class of functions are the radial
distributions gMM' (r) which are obtained by averaging
over molecular orientations, i. e. ,
PMPM,gMM' (r) = (NM(NM, - fJ MM ,) fJ(RlM) fJ(R2M' - r Further,
= f J
d 1M d2M' fJ(R 1M ) fJ(R2M' - r) P~2Jt, (1M' 2M'),
(2.1)
where RiM is the location of the center of the ith mole-
cule of type M; there are NM molecules of type M in a
volume V, PM = (NMI V), and the pointed brackets denote
the equilibrium ensemble average. In the absence of
orientational correlations between a pair of molecules
r---;-~"""""'71(PMPM,IS"2MS"2M' )gMM' (I RlM -R 2M ,I).
(2.2)
where OM is 1 or 411 or 8112 depending on whether mole-
cules of type M are spherical or linear or nonlinear,
respectively.
An auxiliary correlation function that plays an im-
portant role in our analysis is the cavity distribution
function YMM' (1.\(, 2M'), which is defined by
p~2J, (1M' 2M') = (PMPM' IO.\(S"2M') YMM' (1.\(, 2M,)
x exp[ - u.\fM' (1M' 2M, )lkB TJ. (2.3)
Here, UMM ' (1M' 2M,) denotes the potential energy function
which governs the interactions between two molecules,
one of species M and the other of species M', and kB T
is Boltzmann's constant times the temperature. As
seen from Eq. (2.3), Y.\fM' (1M' 2M,) is formed by remov-
ing the multiplicative Boltzmann factor from p~~, (1M'
2M')' From the cluster series for plfJ, (1M' 2M') it fol-
lows that YMM' (1M' 2M,) differs from unity (the uncor-
related ideal gas result) only because the tagged mole-
cules 1M and 2M' interact with neighboring particles in
the condensed phase. Indeed, (PMPM' 1S"2.\(S"2M, ) YMM' (1M'
2M,) is a pair distribution function P~2J, (1M' 2 M') for two
cavity particles. A cavity particle of type M is just like
a molecule of species M in the way it interacts with
molecules, However, it is distinguished from actual
molecules by the fact that it does not interact with other
cavities. These cavity distributions playa central role
in the theory of chemical equilbrium and conformational
structures of molecules in condensed phases. 23,24 We
shall see shortly, as Ben-Naim has noted before us, 10
that these cavity distribution functions also playa cen-
tral role in the theory of hydrophobic correlations.
In our theory for aqueous solutions of apolar solute
J. Chern. Phys., Vol. 67, No.8, 15 October 1977
3685
species we imagine that molecules like methane are
spherical particles which interact with water via a pair
potential uAw( I RIA - R 2w I ) that depends on only the dis-
tance between the oxygen nucleus in the water molecule
and the center of the apolar species (the C nucleus for
CH 4 ). Throughout this article the label A denotes a
spherical apolar species, and W stands for water.
Note that the choice of molecular centers is arbitrary
in classical equilibrium statistical mechanics. We
take the oxygen nucleus as the "center" of an H20 mole-
cule. Within the framework of this model
(2.4)
and
(2.5)
pi2~(1Ao 2w) = (PAPwI8112) YAw(R 1Ao 2w)
l
x exp[ - uAW ( IR1A -R 2w )/kB TJ. (2.6)
The orientational correlations in pi2~(1A' 2w) arise only
from the indirect interactions that make YAw(R IA , 2w)
different from unity. Thus,
(2.7)
where YAW(r) is the A W radial cavity distribution ob-
tained by averaging over the orientations of the water
cavity.
B. Model and basic perturbation theory concepts
As noted in the Introduction we will make no state-
ments about how water molecules interact with one an-
other. However, to describe properties associated
with spherical apolar solute molecules we must say
something about both A-A and A- W interactions. We
take the obvious Lennard-Jones model for the A-A po-
tential
(2.8)
where EA and (JA are the generally accepted Lennard-
Jones parameters for molecules of type A. For ex-
ample, the values for methane are 25
(JM_ =3.7 A,
EM.lkB = 148 OK.
The A- W water interactions are also modeled as spher-
ical potentials
uAw (1 A, 2w) =uAw(IR IA -R 2w l), (2.9)
and we imagine that uA w( r) can be characterized with
only two parameters EAW and (JAW' so that
uAW(r) =EAW~r/(JAW)'
where (x) is a dimensionless function of a dimension-
less variable x. If we took the Lennard-Jones form,
then (x) =4 (X-12 - x-6).
Both uAA(r) and uAW(r) have attractive and repulsive
portions; see Fig. 1. Let r~o~. denote the location of
the minimum in uJ(J(' (r), let - E MM , be the energy at that
minimum, and take the zero of energy to correspond to
3686 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
O~---4-r-----= __
d AA ", 2r A'" O"A
d AW '" rA +rw '" rA +1.35.8.
FIG. 1. Model pair potentials for A-A and A-W interactions.
uAfJ.I' (r) is the total potential for particles of type M and M'
separated by a distance r. [A particles are spherical, and it
is assumed that their interactions with water (W particles) are
spherically symmetric.] The repulsive reference potential is
u1OJ, (r); the hard-sphere potential associated with this repul-
sive interaction is [u1OJ.(r)]HS; the perturbation is u).lJ.(r). The
radii of A particles and water are O"A/2 and r W' respectively,
where O"A is the Lennard-Jones 0" parameter for spherical spe-
cies of type A, and r w is 1. 35 A. The energy ~ A is the Len-
nard-Jones ~ parameter for A particles. The perturbation en-
ergy parameter for A-W interactions ~AW cannot be as easily
estimated.
(00). Then the unique division of u MM' (r) into the
U MM '
short-ranged repulsive portion u1~. (r) and the longer-
ranged attractive part U11~. (r) is 2 o-22
u1~.(r)=EMM' + U MM .(r), r<r1~"
=0,
and
U 11~. (r) = - EMM , r<r1~ ,
= UMM .(r), r > r1~
See Fig. 1 and also see recent texts 22 ,26,27 for a discus-
sion of this separation.
For most liquids the short-ranged repulsions are the
only interactions that are quickly varying functions of
the interparticle separations. Since particles are very
close together at liquid densities, quickly varying in-
teractions dominate the energetics involved in displac-
ing the positions of particles. As a result, the inter-
particle structure for most liquids is dominated by the
repulsive forces. Mathematically, this physical state-
ment means that
where g~O~, (r) is the reference system radial distribu-
tion function-the distribution function for the hypotheti-
cal fluid in which u!1~,(r)=O, or equivalently uMM.(r)
= u 1~, (r).
Note that the motivation for Eq. (2.11) relies on the
condition that u l7~. (r) contains all the quickly varying
interactions. If the reference interaction did not con-
tain all of these interactions, we could not expect Eq.
(2.11) to be accurate. The potential separation in Eq.
(2.10) seems to satisfy the criterion for many systems.
Detailed computations 20 -22,25 have verified the remark-
J. Chern. Phys., Vol. 67, No.8, 15 October 1977
able accuracy of Eq. (2.11). [To appreciate the im-
portance of the criterion note that both the potential
separation of Barker and Henderson19 and the earlier
one attributed to McQuarrie and Katz 28 include quickly
varying interactions in their perturbation potentials
u1\:,(r). As a result both separations yield perturba-
tion theories which fail to describe the structure of
dense fluids with their reference system (2.11), and
both yield comparably poor results when thermodynafl1ic
properties are properly calculated from first-order
perturbation theory. See Chap. 6 of Ref. 22 and refer-
ence cited therein.]
Of course, liquid water cannot (in any straightfor-
ward way) be treated with Eq. (2.11). However, we
believe the true A-A and A- W interactions contain no
specific strong attractions. Thus, Eq. (2.11) should be
accurate when applied to A-A and A- W correlation
functions. In particular,
gAA(r; UAA ' uAW , UwW)zgAA(r; ui~, uio~, UWW )
=gi~(r), (2.12a)
and
gAW(r; U AA ' uAW , uWW)::::gAW(r; ui~, uio~, Uww)
=gio~(r). (2.12b)
The reference system, labeled with superscript 0' s in
Eqs. (2.12), is the fluid in which attractions are ne-
glected in the A-A and A- W interactions, but inter-
actions between water molecules are treated exactly.
Thus, g ~O~( r) is the oxygen-oxygen radial distribution
(2.10a) between real water molecules when the hypothetical
reference system A particles are dissolved in water.
Since the solubility of apolar species in water is very
low, the g~~(r) is the same as that for pure water;
hence,
(2. lOb)
g ~o~( r) = oxygen-oxygen radial distribution (2.12c)
for pure liquid water.
The thermodynamic statement that corresponds to the
structural Eqs. (2.12) is the standard first-order per-
turbation theory formula (the so-called high tempera-
ture approximation)22
+PAPW f drg~O~(r)uil~(r), (2.13)
where F denotes the Helmholtz free energy, and the A'S
(2. 11) indicate excess properties with respect to the ideal gas
at the same temperature, denSities, and volume v.
The chemical potential for species A, !lA, is thus given
by
AJ.i.A:::: AgiO) +Pw f dr g iO~(r) u~l~(r) + 0 (PA), (2.14)
where the terms of the order of PA, 0 (PA), are negli-
gible for the concentrations at which apolar species can
be dissolved in liquid water. Indeed, in all the calcula-
tions we perform in this article J.i.A refers to the chemi-
cal potential of A in liquid water in the limit of infinite
dilution of solutes. Similarly, gAW(r) and gAA(r) refer
 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
to the A- Wand A-A radial distribution functions for
apolar solutes in water at infinitesimal solute concen-
trations, respectively.
According to Eqs. (2.12) and (2.14) the basic theo-
retical problem is the description of the structural and
thermodynamic properties associated with the reference
system: repulsive spherical particles in liquid water.
A major step towards the solution is taken when it is
recognized that the problem is closely related to the
statistical mechanics of hard spheres dissolved in wa-
ter. In particular, suppose g 1~, (r) is the radial dis-
tribution function for two particles that interact with the
repulsive potential u 1~, (r). Then, to an excellent ap-
proximation2o, 22
g1~' (r) =[Y1~, (r)l HS exp[ - u1~, (r)/k B Tl,
where [ Y1~, (r)l HS is the reference hard-sphere cavity
distribution function. The diameters for the hard
spheres dMM, are determined by solving a self-consis-
tent eq uation20 , 22
where [u1~,(r)lHS is the hard-sphere potential with
diameter dMM ,. The solutions yield diameters which
depend weakly on temperature and density. For many
applications this temperature and density dependence
is crucial to the quantitative success of Eq. (2.15) and
its ramifications; see, for example, the discussion in
Chap. 6 of Ref. 22. However, for the principal appli-
cations in this article the temperature and density de-
pendence is of little consequence.
According to Eqs. (2.15) and (2.16) the hard-sphere
and repulsive reference system gMM' (r)'s are identical
except for r values very close to particle contact dMM ,;
and even then the areas under the two radial distribu-
tions are identical. Analysis of these facts 20 -22 leads to
where once again [0 .0 1HS indicates that the term en-
closed by the brackets is evaluated as if the A particles
are actually hard spheres with diameter d AA , and that
they interact with water by a hard-sphere potential
which prevents an A particle from approaching an oxy-
gen by a distance less than dAW ' Thus, as far as the
thermodynamic properties are concerned we need to
consider only the water structure in the vicinity of a
hard sphere. Since the quantities we calculate from
this hard-sphere model are not very sensitive to the
temperature and density dependence of dAA and dAW ,
we fix these diameters according to
where <TA is the Lennard-Jones <T for spherical particles
of type A, and
dAW =(<TA/2) + rw
=(<TA/2) + 1. 35 A,
J. Chern. Phys., Vol. 67, No.8, 15 October 1977
3687
where the second equality identifies 1.35 A as the van
der Waals' radius of water rw. (Any value within - 0.1
A of 1. 35 A will not alter the results reported in this
article. )
Notice that the second term in Eq. (2.14') contains a
mean field term-the refe.rence system average of the
perturbation. Even when the structural properties of
the fluid are determined entirely by the reference sys-
tem interactions, the perturbation still contributes in a
Significant (though simple) way to the thermodynamics.
A similar statement is true concerning the cavity dis-
tributions YMM' (r). In particular, by combining Eqs.
(2.11) and (2.10) with
gAA(r) =YAA (r) exp[ - uAA (r)/k B Tl
(2.15) one findS
YAA (r)'" Yi~(r) exp[ + U i~ (r)/k B Tl. (2. 18)
AccordingtoEq. (2.15)Yi~(rJ"'[Yi~(r)lHs, sothatEq.
(2.18) becomes
YAA (r)'" [Yi~(r)l HS exp [+ ui~(r)/kB Tl. (2.19)
Similarly,
YAW( r) '" [ Y1~( r)l HS exp [+ u il~(r)/kB T l. (2.20)
(2.16)
Hence, the cavity distributions YAA(r) and YAW(r) differ
from those appropriate to hard spheres dissolved in
water. The difference is a Simple mean field Boltz-
mann factor.
In the next part of this section we will describe a
scheme for calculating the hard sphere A-A ahd A- W
cavity distributions. But first it is important to note
that these functions also describe the thermodynamic
properties associated with hard spheres dissolved in
water as well as the interparticle correlations. The
connection to thermodynamics is established from the
functional derivative relation
(2.21)
where [1 +f MM' (r) 1is the Boltzmann factor for a spheri-
(2.14')
cal pair potential between species M and M'. When the
interactions are hard-sphere potentials, the Boltzmann
factor is a unit step function, and integration of Eq.
(2.21) is straightforward, yielding an excess free en-
ergy
[aF(O) /k B T vl lIB =- PA ln(l - ~1Tpwr~)+ 21TPAPW
UA
xf d<T(rw+ <T/2)2CAW (rW+ 0/2) + O(P~),
O
(2.22)
where CAw (rw+o/2) is the contact value of [g~O~(r)lHS
when the hard sphere A particle has diameter <T. The
first term on the right-hand side of Eq. (2. 22) is the
constant of integration. It describes the free energy
(2. 17a)
when the hard spheres are simply points occupying no
volume. The integral describes the reversible work
expended in creating the particle with diameter <TA
The excess chemical potential (with respect to the ideal
gas) for the hard spheres at infinite dilution in water
(2. 17b) can be obtained by differentiation of Eq. (2. 22). The
3688 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
result is the well-known formula 16
[lllliO)] lIS =- kB Tln(1 -t7Tpwr~)
+27TPA k B T j~aA da(rw+a/2)2CAW(rW+a/2).
(2.23)
An alternative connection between the chemical po-
tential and correlation functions is obtained from the
following argument: The reversible work required to
move two A-particle cavities which are initially in-
finitely far apart to an interparticle separation of r is
-kBTlnYAA(r). Further, when the A particles are hard
spheres the reversible work to bring two cavities from
infinity to r= 0 is the same as the reversible work re-
quired to remove one of them from the system. These
facts imply
which can be verified with mathematical arguments29
as well as the physical one we have given.
C. Approximate theory for A-Wand A-A pair
correlations
We have established that the principal problem con-
fronting us is the description of the radial distribution
functions associated with hard-sphere particles and
cavities dissolved at infinite dilution in water. We now
present a simple theory for these functions.
To begin our analysis it is convenient to subtract
the ideal gas contributions to the distribution functions
and define the radial pair correlation functions
and
Next we define the functions cAW(r) and cAA(r) through
the following Ornstein-Zernike-like equations:
hAW(r) =cAW(r)+Pw f dr' cAW ( Ir -r' I)hww(r')
and
hAA(r) =cAA(r) +Pw f dr'cAW(lr-r' l)hwA(r'),
(2. 26b)
where hww(r) =g~~(r) -1 is the radial pair correlation
function for pure liquid water.
Notice that Eqs. (2.26) do not refer to full orienta-
tion dependent pair correlation functions. For this
reason these equations differ from the usual Ornstein-
Zernike (OZ) expressions that would be appropriate at
infinite dilution of A particles in water. Similarly,
cAW(r) differs from the usual OZ direct correlation func-
tion which depends upon the orientational coordinates
of a water molecule. Equation (2.26) are spherical
analogs of the OZ equation. While the latter can be de-
rived as a topological rearrangement of the cluster ex-
pansions for pair correlation functions, 30 Eqs. (2.26)
do not have the same cluster diagrammatic interpreta-
tion. The OZ equation and Eqs. (2.26) are connected
J. Chern. Phys., Vol. 67, No.8, 15 October 1977
by their physical Similarity rather than a mathematical
sim ilarity.
There is no doubt that cAW(r) and cAA(r) are well de-
fined mathematically. Indeed, the Fourier transforma-
tion of Eqs. (2.26) yield
hAW(k) =~Aw(k)[l + Pwhww(k)] (2.27a)
and
(2.27b)
where the caret indicates the Fourier transform, e. g., .
hww(k) = f dre- ik ' r[g~~(r) -1]. (2.28)
The term in square brackets in Eq. (2. 27a) is the oxy-
gen-oxygen structure factor for pure water. It is neces-
sarily finite and positive. Hence, Eq. (2. 27a) can be in-
(2.24) verted to solve for cAw(k) and thus cAW(r) in terms of
well behaved quantities. Similarly, it follows that
cAA(r) is also well defined.
The physical meaning of these radial direct correla-
tion functions follows from an inspection of Eqs. (2.26).
That equation ascribes the following mechanism to the
formation of A- W radial pair correlations: Either an
A and a Ware correlated directly (the first term on the
right-hand side of Eq. (2.26a)], or an A is directly cor-
related to an intermediate W which in turn is correlated
to the tagged W (the second term). A similar interpre-
tation of Eq. (2. 26b) is also established. Ornstein and
Zernike introduced the idea of direct correlation func-
tions because they felt that such functions should be
short ranged-essentially zero beyond distances larger
than the range of the interparticle pair potential. The
(2.25a) literal interpretation of these ideas suggests
(2. 29a)
(2. 25b) and
(2.29b)
These approximate equations can be combined with the
(2.26a) exact boundary conditions
(2.29c)
and
(2. 29d)
to close the Ornstein-Zernike-like integral equations
(2.26). To solve these equations one must determine
the cAW(r) functions which, when inserted into Eq.
(2. 26a), satisfies Eq. (2. 29c). Once determined, Eq.
(2. 26a) can be integrated [most easily by inverting the
Fourier transform in Eq. (2. 27a)] to yield hAW(r) for
r > (aA /2) + rw' Then, Eqs. (2. 27b), (2.29b), and
(2. 29d) give
[gi~(r)]HS=O, r<aA,
=1+pw fdr'cAW(lr-r' l)hwA(r'), r>aA
(2.30)
The integral in the second equality is conveniently per-
formed by noting that it is the inverse Fourier trans-
form of [c Aw (k)P[1 +Pwhww(k)].
 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
Thus, our theory for A- Wand A-A pair correlations
is the Ornstein-Zernike-like integral equation [Eqs.
(2.26)] with the closure relations (2.29). Our motiva-
tion for the theory is the physical association of CA w( r)
and cAA(r) with direct correlations and the belief that
these direct correlations are short ranged. It is pos-
sible to support this motivation with further mathe-
matical manipulations. Indeed, we have shown else-
where 30 that is is possible to derive our integral equa-
tion with a topological reduction which eliminates the
intractable direct W- W interactions in favor of the ex-
perimentally known hww( r), and then a partial summation
of the exact cluster series for the A- Wand A-A pair
correlation functions. It is also possible to generate
our integral equation by applying Percus' functional
expansion techniques. 17 It is probably more relevant
to note that the physical arguments used to obtain our
integral equation can also be used to obtain the Per-
cus-yevick integral equation for' the hard sphere liquid,
and the RISM integral equation for liquids composed of
hard core but aspherical molecules. The Percus-
yevick theory provides a reliable qualitative descrip-
tion of the hard-sphere fluid 22 26 and the RISM equation
gives a reliable description of pair correlations in highly
ordered liquids composed of highly aspherical mole-
cules. 31 However, these considerations do not establish
the validity of our integral equation. The theory must
be judged by the comparison of its predictions with avail
able experimental data in Sec. III.
The integral equation can be solved by a variety of
techniques. The method we have employed is the fol-
lowing variational procedure. Let the functional 1[ CAW]
be defined as
1= f dr cAW(r) + ~ J
dr ciw(r)
+[2(21T)3]-1 Pw Sdk[cAW(k)]2 h ww(k).
Functional differentiation shows that
51 /5c AW (r) =[gio~(r)] lIS'
As a result, Eq. (2. 29c) implies
5115cAw (r) =0, r<dAW ' (2.33)
This variational equation is equivalent to Eqs. (2.26)-
(2.29). To apply the equation we let
n max
cAW(r) = L,,=0 cn[(r-dAw)/dAW] n, r <dAW ,
This representation reduces Eq. (2.33) to a set of cou-
pled linear algebraic equations
(allacn)=O, n=1,2, ... , ~ax'
Once the coefficients are determined Eq. (2.34) is in-
serted into Eq. (2. 27a), and [giO~(r)] lIS is computed for
r>(aA/2)+rw' Then [giO~(r)]1IS is used inEq. (2.30)
to compute [gi~(r)]HS for r>aA
As an illustration of the magnitude of the errors that
may be expected from Eqs. (2.26)-(2.30) we have ap-
plied this theory to a solution in which the solvent
J. Chern. Phys., Vol. 67, No.8, 15 October 1977
3689
molecules are hard spheres of diameter 2.7 A= 2rw,
and the solute molecules are also hard spheres of
diameter a A = 2.7 A. The exact hard-sphere correla-
tion function was calculated by the method of Verlet
and Weis. 21.22 At 8pr~ = 0.656 (the density of liquid
water at one atmosphere total pressure and 25C we
find gAA(a) =2.72, and gAs(a)=2.66. Here S refers to
the hard-sphere solvent molecule. The exact contact
value can be estimated from the Carnahan-Starling
equation of state. 21 22 It is 2.93. Thus, the errors
near contact are about 10% of the exact value. Away
from contact the disparity between gAS(r) and gAA (r)
rapidly disappears. Indeed, at the water density gAA (r)
and gA s(r) are indistinguishable for r> 3.5 A. If the
solvent density is raised to 8pr~ = 0. 9, the Percus-
Yevick-like theory we have presented yields gAA (a)
=4.27, and gAS(a) =4. 28. The exact contact value is
5.17. It should be noted however that liquid water never
attains densities this high at 1 atm total pressure.
All the aqueous solution calculations reported herein
use the hww(k) measured by Narten and Levy at 1 atm
pressure.14 For computations at temperatures other
than those which Narten and Levy studied we interpolated
their results at T=4, 25, 50, and 75C at each wave
vector. (The Narten-Levy data at 20C was excluded
from the interpolation because it is not of the same high
precision as the data at the other temperatures. 14) The
denSity of water Pw appearing in the integral equation
was obtained from the equation of state for liquid water
at 1 atm pressure. 32
An example of our results is shown in Figs. 2 and 3.
Table I contains the coefficients cn for several diameters
aA (We find that for aA $ 5 A the computations are un-
(2. 31)
CT
A
=3.71i
T =25C
(2.32) 3.0
-;::: 2.0
<!
<!
0>
1.0 -----~
I
(2.34) I
I
ill W ~ W W W ID 00 ~
r (21)
(2. 35)
FIG. 2. The A-A radial distribution function gAA (r) for spher-
ical repulsive A particles of diameter 3.7 A in water at 1 atm
pressure and 25 C. The solid line is calculated from the solu-
tion to Eq. (2.29), It is appropriate to hard-sphere A particles
dissolved in water at infinite dilution of solutes. The dashed
line is obtained from the hard-sphere result and Eq. (2. 15)
with ul1(r) taken as the repulsive part of the Lennard-Jones
potential. Thus, the dashed line is appropriate to soft sphere
A particles.
3690 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect

knowledge of [giO~(r)l HS and [gi~(r)l HS outside the hard

G"A=30A cores provides a lot of information about [Yi~(r)] HS in-
G"A = 5.0 A
side the hard core, and we can utilize that information
to construct an interpolation formula for l y i~ (r) 1HS'
In particular, note that In[ Yi~(O)]lfs =(!lIlA/kB T) [Eq.
(2. 24)]. The chemical potential can be calculated from
the hard sphere contact value of [gio~(r)]lfs by applying
Eq. (2.23). Further, In[Yi~(r)]HS is a smooth function
and its second derivative is continuous near r=aA
(These analytic ity conditions are readily established
from the cluster expansion for cavity distribution func-
tions.) Hence, its value and first two derivatives at aA
can be computed from those values of [gi~(r)]HS at con-
tact, i. e., r= a A+' As a result we write

o.oL----;::;o~0---;l0';;-------,,2~'O,..-"3~O,..---;4~'O:----;5~'O:----;6~.o:--.-J InVAA(r):::: L 3
n=O
(r a)"
an ~ , for r <aA,
aA
(2.38)
( r - rw - G"A 12)( )\ )
where the coefficients an are fixed by demanding that
FIG. 3. The A-W radial distribution functions gAW(r) for hard- In[y i~ (r)] HS and its first two derivatives are continuous,
sphere A particles dissolved in liquid water at 1 atm pressure
and that In[y~(O)]HS is given by Eq. (2.24) with !lilA
and 20C and infinite dilution of solutes. The parameter (FA
specifies the diameter of the A particle. Note the abscissa computed from Eq. (2.23). The an's are tabulated for
scale varie s with (FA' spheres of several diameters in Table II. Figure 4 pro-
vides a plot of a representative [Yl~(r)] HS computed in
this way, and a comparison of it with [Yi~(r)] HS
changed when n max 2:: 3, so we report the cn's for ~ax = 3. ) :::: -cAA(r).
We postpone a full discussion of the significant features
of these results until after the comparison with experi- D. Multipoint cavity disfribution functions and
ment is made in Sec. IlL molecules with internal degrees of freedom

While we do not use them in this article, it is fre-
quently also of interest to calculate pair correlations
between apolar solutes of different types. These cor-
relation functions hAA (r) can be calculated directly from
the coefficients for cAW(r) and cA'W(r) presented in Table
1. For completeness we present the relevant formula
now
The theory presented above may be extended to study
hydrophobic phenomena associated with molecules which
are nonspherical and nonrigid, such as Simple hydro-
carbons. These molecules may be viewed as a collec-
tion of overlapping "atoms" or A particles. The mole-
TABLE I. Coefficients for expansion of cAW(r) =L:~=oC"[(r
-dAW)/dAW ]". r<d AW'

T (oC) (FA (A) Co Cj c2 c3

=1 +Pw(21fr3f dke ikor
20 2.5 - 2.713 7.732 O. 756 2.111
3.0 -2.817 8.540 -7.698 - 5. 628
x cAw(k) cA' w(k)[1 +Pwhww(k)], r> d AA .
3.5 - 3.008 6.950 -22.620 - 18. 341
(2.36) 4.0 - 3.197 6.171 - 32.615 -26.329
In the computations comparing theory and experi- 4.5 - 3. 282 7.540 - 34.631 -27.937
5.0 - 3. 264 10.294 - 32.327 - 26.931
ment we need the cavity distribution functions[y~(r)] HS
and [yiO~(r)] HS as well as the radial distribution func- 25 2.5 -2.709 7.710 0.806 2.317
tions [giO~(r)] HS and [gi~(r)] HS' Outside their respec- 3.0 -2.811 8.518 - 7. 514 - 5. 244
tive hard cores the y's and g's are identical. To cal- 3.5 -2.996 6.927 - 22. 370 -17.915
4.0 - 3.182 6.083 - 32. 532 - 26. llO
culate the cavity functions inside the hard core we note
4.5 - 3. 269 7.337 - 34.862 - 28.064
that Eqs. (2.26) and (2.29) are satisfied if 5.0 - 3. 255 9.996 - 32.787 -27.333
[YiO~(r)]HS:::: - cAW(r), r aA /2)+r w, 30 2.5 - 2.702 7.676 0.865 2.526
3.0 - 2.801 8.471 -7.336 - 4.874
and
3.5 -2.981 6.881 - 22. 083 -17.470
[ y i~ (r) 1HS l' - CAA (r) , r < aA (2.37) 4.0 - 3.162 5.979 -32.358 - 25.830
Ipoor a,pproximat ion I 4.5 - 3. 251 7.116 - 34.970 - 28.105
5.0 -3.241 9.789 - 33.100 -27.631
However, as indicated Eq. (2.37) is not accurate enough
to be useful. The inaccuracy is a well-known deficiency 50 2.5 -2.664 7.455 0.839 2.856
of Percus-Yevick-like approximations. [Indeed, the 3.0 -2.755 8.189 - 6.889 - 3. 993
3.5 -2.918 6.679 - 20.886 - 16. 024
PY theory for hard cores in one dimension yields the
4.0 - 3. 085 5.686 - 31. ll9 - 24.573
exactg(r) and thus y(r) when r>a; but the PY ap-
4.5 - 3.180 6.635 -34.331 -27.611
proximation, y(r) =- c(r) when r< a, is at best only qual- 5.0 - 3.183 8.834 - 32.964 -27.797
itatively accurate in one dimension.] Fortunately, the

J. Chern. Phys., Vol. 67, No.8, 15 October 1977

 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect 3691

TABLE II. Coefficients for expansion of In[YAA(r)]HS Hon for an isolated (ideal gas) molecule, the abbrevia-
"'~~oa"[(r-uA)/uAl". r:suA' tions f d 1M denotes the nM-fold integration over all ny
vectors which determine the molecular arrangement,
UA (A) T (OC) ao al a2 a3
and
3.0 20 0.881 - 3.191 -0.200 -3.491
25 0.887 - 3.179 - 0.189 - 3. 478 Y *(1
M M) -- YM
*(r(1)
1M,, ("M
riM
30 0.895 - 3.161 - 0.184 -3.466 =nM-particle cavity distribution
35 0.904 -3.140 - 0.184 - 3. 454
function for nM cavity particles. (2.40)
40 0.912 -3.118 - 0.189 - 3. 442
45 0.919 -3.010 - 0.197 -3.427 The derivation and full explanation of Eq. (2.39) is
50 0.923 - 3. 076 -0.207 -3.408 given in Refs. 23 and 24. As an example suppose M
3.5 20 0.960 -3.894 - 0.890 -6.120 refers to n- butane, H3C-CH 2 -CH 2 -CH 3 As far as
25 0.965 -3.897 - 0.958 -6.164 liquid water is concerned this molecule might as well
30 0.971 - 3.897 -1.044 -6.214 be four overlapping CH 4 molecules. We can define an
35 0.977 - 3.895 -1.135 - 6. 262 A cavity to be the type of cavity particle which is as-
40 0.982 -3.890 -1.222 -6.297
sociated with a CH 4 molecule. Then yz(1 M ) for n-bu-
45 0.985 - 3.881 -1. 293 - 6. 313
50 0.987 -3.870 - 1. 340 - 6.301
tane is the four-particle cavity distributioR function for
four A cavities located at rW, rft>, rm, and rW. In
3.7 20 0.993 -4.204 - 0.650 -6.811 the dilute gas phase, cavity distributions are simply
25 0.996 -4.221 - 0.777 - 6.897
unity and sM(1 M)- s10)(1 M). However, when the mole-
30 0.999 -4.236 - O. 925 - 6. 991
35 1.001 -4.249 -1. 079 - 7.080 cule M is dissolved in a liquid solvent, y;(1 M) is very
40 1. 003 -4.257 -1. 222 -7.151 different than unity. Knowledge of y~(1M) for a particu-
45 1.004 -4.259 -1. 336 -7.191 lar solvent together with Eq. (2.39) provides the means
50 1. 003 -4.253 -1. 409 -7.189 to calculate the conformational structures of nonrigid
4.0 20 1. 045 -4.569 -1. 209 -9.084 molecules when the molecules are immersed in the
25 1. 043 -4.613 -1. 418 - 9. 222 liquid solvent.
30 1. 039 -4.659 -1. 658 - 9. 372
- 9. 512
The thermodynamic consequences of Eq. (2.39) are
35 1. 035 -4.703 -1. 903
40 1. 031 -4.738 - 2.125 - 9. 623 discussed in Ref. 24. By differentiating the series for
45 1. 027 -4.761 -2.298 -9.684 the Helmholtz free energy given in that article one can
50 1. 022 -4.766 -2.340 -9.677
4.5 20 1. 139 - 5. 271 -2.097 -13.298
25 1.126 - 5. 365 -2.454 -13.530
30 1. 110 ;- 5. 466 -2.854 -13.774
35 1. 093 -5.564 - 3. 258 -14.002
40 1. 077 -5.646 -3.620 -14.179
45 1. 063 - 5. 703 - 3.881 -14.267
50 1.053 - 5.724 -3.998 - 14.226
5.0 20 1.227 -5.935 -3.455 -18.678
25 1.204 -6.069 - 3. 936 -18.992
30 1. 177 -6.210 -4.462 -19.310
35 1.150 - 6. 344 -4.986 -19.601
40 1.125 - 6. 455 - 5.443 -19.819
45 1.104 - 6. 528 -5.759 -19.910
50 1. 091 - 6.550 - 5.866 -19.819

cules are held together by chemical bonds. But the

bonding does not force the molecules to be rigid. In-
deed, there may be appreciable conformational de-
grees of freedom.
Imagine that a molecule of type M is composed of nM
overlapping A particles. The configuration of the A par-
ticles in molecules of type M is 1M = (rgj, rW, ... ,
r~~, where rt~) is the location of the ath particle
(which mayor may not be of the same type as the other
nM -1 particles forming the molecule). The probability lO~--71~O--~2~O--~3~O~--4~O~~50
distribution for finding a molecule in this arrange- r (1\)
ment is23 24
FIG. 4; The cavity distribution YAA(r) computed from Eqs.
(2.38) and (2.29) (the solid line) and from Eqs. (2.37) and
(2.39) (2.29) (the dashed line). The cavity A particle has a hard core
diameter of uA '" 3.7 A. and the temperature and pressure of
where s10)(1 M) is the intramolecular distribution func- the liquid water solvent is 25C and 1 atm. respectively.

J. Chem. Phys., Vol. 67, No.8, 15 October 1977

3692 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect

straightforwardly derive an equation for 6./l M , the ex- Eq. (2.14) which involves the van der Waals radii and
cess (with respect to the ideal gas) chemical potential is thus independent of any adjustable parameters. By
for molecular species M dissolved in a liquid solvent numerical differentiation of the theoretical results in
at infinite solute dilution. The result is Table III one finds the theoretical prediction of the ex-
nM cess partial molar entropy of solution
6./l M = L
i=1
6./l iM - kB T lnq:, (2.41)
6.SMe =- (86./l M .I 8T)p
where of methane at 25C and infinite dilution to be

(2.42) [6.~e]theOrY, =- 20.7 cal/mole deg.

hard
sphere

and 6./l iM is the infinite dilution excess chemical poten- This is to be compared with the experimental results of
tial for i th of the nM particles which are bound together Ben-Naim and co-workers 1o
to make a molecule M. For example, the sum of 6./Ji/s
for n-butane would be 46./l Me , where 6./l Me is the meth- [6.SMe ]oxpt. = -15.5 cal/mole deg,
ane excess chemical potential. For the special case in and of Morrison and Billett33
which molecule M is rigid Eq. (2.41) reduces to Ben-
Naim's result10 [6.SMe ]expt, = -17.0 cal/mole deg.
nM The latter number is obtained from numerical differ-
6./l M I
Irlgldmoleculel
L 6./l i.1
iM - kB Tlny~(1M) (2.43) entiation of the published Ostwald coefficients.
Closer agreement with experiment can be obtained by
III. COMPARISON OF THEORY WITH EXPERIMENT accounting for the fact that the diameter for the hard
sphere model is actually temperature dependent. The
A. Solubility of methane in water
temperature dependence arises because the actual re-
Several theories for the description of the solubility pulsive potentials are continuous interactions. See Eq.
of simple apolar solutes in liquid water have been pro- (2. 16). As the temperature is raised pairs of particles
posed. 7- 10,13 It is important to note that any micro- can approach one another more closely. Thus, dO' AIdT
scopic theory for 6./l A will be very sensitive to the < O. The size of this derivative can be estimated from
choice of the mean field perturbation uil~(r). This is information tabulated by Verlet and Weis. 21 For methane
because the second term in Eq. (2.14) is of the same one finds
magnitude as the first, but with opposite sign. Further-
daMeldT'" -1. 3x 10-3 A/deg.
more, except for estimates of van der Waals' radii,
the interaction potential energies between apolar solute This number can be combined with
molecules of interest and water are not well known.
Given the uncertainty in u iV(r) comparison with ex-
[6.SMe ] theorY, = [6.~eltheorY, _( 8:;:Me) daMe
dT '
continuous hard Me T.P
repulsion sphere
perimental gas solubilities alone cannot be considered
a conclusive test of a theory of hydrophobic phenomena. where the partial derivative is evaluated from our theory
However, it is surely necessary to demonstrate that and found to be 2.48 kcal/mole A. As a result,
our theory can quantitatively describe experimental gas
solubility data for realistic choices of a slowly varying
perturbation potential u~1~(r). For this purpose we TABLE III. Henry's Law constant kH(T)
consider methane and assume u~1iw(1) is the Lennard- = Pwk B Texp(6./l M.l k B T ) for methane in
Jones perturbation with aMeW =aM .+ 1. 35 A and EMew water.
= (EMeEw)1I2. As stated earlier EM.lk B is 148 K and aM.
is 3.7 A. It is not easy to establish a good estimate of
the parameter Ew (or equivalently EMew )' We treat it as T (oC) Calc. a Expt. b
an adjustable parameter. The Henry's Law constant 20 39.9 40.9
for methane in water can be fit exactly at 25C with our 25 45.7 45.7
theory and a choice of 192 OK for EW/kB' With this val- 30 51. 6 50. 1
ue we obtain the Henry's Law constants kH(T) given in 35 57.0 55.0
Table III. It is seen that once Ew is fixed the tempera- 40 62.4 59.5
ture dependence of k H ( T) is predicted quite well. We 50 71.1 68.6
have found this type of agreement to be typical of the
acalculated from Eqs. (2. 14'), (2.23),
results for other inert gases. and the perturbation potential chosen to
The temperature dependence of the solubility of be the attractive part of the Lennard-
Jones interaction with the parameter
methane in water is a more revealing test of the validity
EMew/kB = 192 OK (see text). The den-
of the theory than the values of the Henry's Law con-
sity of water at 1 atm pressure, Pw, is ob-
stants themselves. This is because the mean field con- tained from equation of state data (Ref.
tribution to 6./l A [the second term in Eq. (2.14)] is only 32).
a weak function of temperature. Therefore, the tem- bExperimental data are those of Morri-
perature derivative is dominated by the first term in son and Billett (Ref. 33).

J. Chern. Phys., Vol. 67, No.8, 15 October 1977

 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect 3693

[.6.~el theory, = - 17.5 cal/mole deg.

contlnuous
repulsion -2.0

-
<lI>Q)
Thus, the continuous nature of real repulsions as op- 0
~o
posed to hard core interactions has an effect of rough- ~ ethane
ly 3 e. u. on .6.~e'
-3.0
Another point becomes apparent from this calcula-
tion. Any disagreement between experiment and our
theoretical prediction of .6./l Me can be attributed solely
Q; 0
to uncertainties in the interactions between water mole- "0 0
E -4.0
cules and apolar solute particles. ...... CbQ)
"0

= u

B. Ben-Nairn's measure of the hydrophobic

interaction: Ethane
;:::1;
<J:
l -5.0
~ propane

Ben-Naimlo has advocated consideration of the quan-

tity

(3.1) -6.0 ........

.... -- --....
- - - - propane, theory
as a measure of the strength of the hydrophobic inter- with superposition
approximation
action. Comparison of Eq. (3.1) with (2.41) shows that
-7.0
the terms involving the excess chemical potentials of
the individual cavity particles are cancelled exactly. As 10 20 30 40 50 60 70
a result the unknown mean field parameters which con- T (Oe)

tribute to .6./l IM do not contribute to liA 1HIl. The cancel-
lation of the .6./l iM 'S is a remarkable virtue of the quan-
tity liA1HIl. It is a measurable thermodynamic property,
but it is independent of unknown parameters and it de-
pends directly upon correlations among apolar spherical
cavity particles in liquid water.
Thus, we can test our theory without requiring any ad-
justable parameters to describe the solute-water inter-
action. For ethane we combine Eqs. (3.1), (2.41) or
equivalently (2.43), and (2.19) to obtain
M~~Il = EMe - kB Tln[y~O~Me(Lc_c)l!lS' (3.2)
where Lc-c is the C-C bond length in ethane 1. 54 A.
To implement Eq. (3. 2) we need to assign values to EMe
and aMe . These are the Lennard-Jones parameters
determined by Verlet and Weis 25 and cited above. Ap-
plying our theory for pair correlations to this model
gives the results shown in Fig. 5 along with the experi-
mental results of Morrison and Billett. 33
The fact that liA~~Il decreases as the temperature is
increased has been taken as evidence that the strength
of the hydrophobic interaction increases as the tem-
perature is increased. 10 Viewed on a microscopic
level this conclusion appears paradoxical. If the hy-
drophobic interaction is a result of the peculiar nature
of liquid water, then one would expect that the hydro-
phobic interaction strength should decrease as the tem-
perature is raised and liquid water becomes less pe-
culiar. We have found that the magnitude of In[Y~~Me
X (L c _ c )] HS actually decreases Slightly as the tempera-
ture is increased, and to a good approximation the whole
temperature dependence of liA~~Il is due to the kB T fac-
tor multiplying In[y~O~Me(Lc_c)]HS'
When first discussed by Ben-Naim lo the motivation
for the study of liA1HI) was to gain information about the
clustering of real apolar solutes (not cavity particles)
FIG. 5. Hydrophobic interaction free energy 6A1H1J for rigid
alkanes. The circles are the experimental results of Morrison
and Billett (Ref. 33). The dashed line represents the results
obtained for propane when the superposition approximation is
used.
in liquid water. This idea has resulted in some confu-
sion when considering
liA~r;~enYI = .6./lblpheny! - 2.6./lbenzene'
This quantity has been incorrectly interpreted in terms
of physical association of pairs of benzene molecule in
water solution. lo However, the interpretation does not
agree with experimental results. 11 There are two theo-
retical reasons why the interpretation is invalid. First,
in order to extract information about physical associa-
tion of pairs of molecules from the value of a cavity
distribution function at one point a very restricted defi-
nition of a "physical dimer" must be adopted and con-
sistently applied. 23 ,24 The second reason has to do with
the fact that covalent radii are significantly smaller
than van der Waals' radii, and cavity distribution func-
tions are very rapidly varying functions of distance.
To examine these pOints quantitatively, assume that
benzene molecules are spheres of diameter a</>, and let
L'I>-</> denote the distance between the centers of the ben-
zene rings in the biphenyl molecule (C 6 Hs)-(C 6Hs)' From
the Lennard-Jones potential for benzene34 we estimate
a</> = 5. 3 A,
and the chemical structure of biphenyl gives
L<I>-</> =4. 2 A.
For 5. 3 A spheres in liquid water our theory for cavity
distributions yields
[y~oJ(5.3 A)/y~oJ(4.2 A)]!IS=3.6/15.4=O.2.

J. Chern. Phys., Vol. 67, No.8, 15 October 1977

3694 l. R. Pratt and D. Chandler: Theory of the hydrophobic effect
Thus, it is grossly incorrect to assume that the cavity
distribution evaluated at L~ _~ is s im ilar in value to that
evaluated at u~. The fact that Yu (r) varies rapidly with
r also makes it very difficult to develop any useful pro-
portionalities between gas phase and liquid phase equi-
librium constants K for physical dimerization of two
benzene molecules. It is possible to write 23 24
In y~ ~ (U<IJ ) =In(Kwate / Kgas)
only when yu(r) does not vary appreciably in the di-
merization region. Thus, one must adopt such a re-
stricted definition of a physical dimer that no appre-
ciable quantity of these dimers would exist.
To apply our theory to 1iA~~;~enYl we use the Lennard-
Jones (lk B for benzene, 34 440 oK, and the value of
Yu(L~_~) cited above. At 20C these numbers yield
[see, for example, Eq. (3.2)]
1iA(b~~henYl =- kB Tlnyu(4. 2 A) =- 719 cal/mole.
This result is in fair agreement with the experimental
value lO
(1iA~~:~.nYl)exPto =-1136 cal/mole.
Any closer agreement would be fortuitous. Benzene is
not a spherical molecule. A model for benzene that is
more realistic than the Lennard-Jones potential must
be employed if one desires a quantitatively accurate
calculation of 1iA~~I~enYl'
C. oA~1) for larger alkane chains
A wealth of experimental solubility data exists for
more complicated hydrocarbons. However, to be able
to study 1iA~HI) for larger molecules we must have a
procedure to construct multipoint cavity distribution
functions from pair cavity distribution functions. The
most widely known such procedure is the superposition
approximation
=
UU(rgJ, r~~, ... , r~~) lny ;(rgj, r~~, ... , r~~If)
where w( r) is InYAA (r). (For simplicity we consider
chain molecules composed of nM identical overlapping
spherical cavity particles.) When applied to the three
body distribution function in simple liquids35 this ap-
proximation has been found to be qualitatively accurate
for configurations in which none of the cavities overlap.
But the applications which we have in mind require
y~(lM) for configurations in which many cavities overlap
significantly. For these configurations the errors in-
curred by Eq. (3. 3) may be enormous. To demonstrate
this fact consider the distribution function for n hard
sphere A cavities. Let wn (Xl' ... , x, ) denote the loga-
rithm of this n-point distribution. When the centers of
two cavities are coincident we have the exact relation,
analogous to Eq. (2.24),
[wn(Xl> x 2, X, )]&1'112 =w(O) + wn_l (x2 X3 x,).
(3.4)
But for the same situation the superposition approxi-
mation gives
J. Chem. Phys., Vol. 67, No.8, 15 October 1977
=W(0)+W~~t)(X2' X3 . . . . . x,,)+ L
i:=3
w(IX2 -Xi I). (3.5)
The superposition approximation overestimates the ef-
fect of the structure of the dense liquid medium by the
overcounting exhibited in Eq. (3.5). As a concrete ex-
ample of the size of the possible errors we show
1iA~~I~ane calculated with the superposition approximation
in Fig. 5. The agreement with experiment33 is terrible.
Since the calculated results for 1iA~~I) agree quite well
with experiment, and since the only additional approxi-
mation employed in this propane calculation was the
superposition approximation, we conc lude that the super-
position approximation can be qualitatively wrong for
configurations in which cavities overlap significantly.
We have investigated several simple alternative theo-
ries for constructing yZ(lM) from the pair function,
These theories are formulated by expressing wM(lM) as
an algebraic function of the pair w(r)'s. wM(lM) is then
required to obey Eq. (3.4) and reduce to the appropriate
asymptotic form whenever one cavity becomes infinitely
removed from the others. We have found that any theo-
ry which eliminates the overcounting in Eq, (3.5) dra-
matically improves the comparison with experimental
1iA ~H I) for alkanes, However, the detailed comparison
depends on the algebraic form adopted for wM(lM)' Un-
fortunately, computer simulation studies of cavity dis-
tributions for three or more cavities in overlapping con-
figurations do not exist. Therefore, we are unable to
judge the relative merits of the different theories over
a wide variety of configurations.
There does exist a molecular dynamics study of
Ryckaert and Bellemans 36 of liquid n-butane. The mod-
el n-butane molecule adopted by these authors consists
of four spherical methyl groups centered at the positions
of the carbon atoms of a real n-butane molecule. The
.carbon-carbon bonds are rigid, and adjacent bonds are
fixed by the tetrahedral angle. Thus, there is only one
conformational degree of freedom, the dihedral angle
(see Fig. 6). Ryckaert and Bellemans report the aver-
age intramolecular potential energy <V() for the non-
rigid model n-butane molecules. In terms of the func-
tions we have defined this average is given by
where we have noted, with IM(), that the intramolecu-
lar configuration 1 M is fixed by A straightforward
0
change of variables yields
<V() = J'-. dSM()V() ,
where SM() is the distribution function for the dihedral
angle. It is given by23
(306)
where c is the normalization constant. Ryckaert and
Bellemans result for (V() provides a simple straight-
forward test of theories for the intramolecular distribu-
tion function.
 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
In liquid water
In n-hexane
In ideal gas
T =25 C 0
1.0
~ for rigid molecules also contain large errors when the
:::;;08
(fl
0.6
04
02
7T
-rrP I,cnr-'-/ \ I
FIG. 6. The intramolecular distribution function vs dihedral
angle <p for n-butane in the ideal gas (dash-dot line). nonasso-
ciated "hydrocarbon" solvent discussed in text (dashed line).
and liquid water (solid line) all at T = 25 'C. The dihedral angle
is defined in the schematic picture of the n-butane molecule.
The trans conformer corresponds to <p = 0; the two gauche con-
formers are localized near <p = 27r/3.
In a separate analysis 37 of this computer simulation
result we have established the following conclusions:
First, when the superposition approximation is applied
to the four point cavity distribution function Y~4HIO[lM(4))]
the calculated change in the average intramolecular po-
tential energy from the ideal gas value is too large by
approximately a factor of 2. Second, the error due to
the superposition approximation may be satisfactorily
avoided by employing a two cavity model of n-butane.
Imagine the methyl sites in a n-butane molecule num-
bered sequentially from 1 through 4 starting at one end
of the molecule. Then we form a two cavity model of
n-butane by replacing methyl sites 1 and 2 by a sphere
midway along the 1-2 bond and replacing the methyl
sites 3 and 4 by another sphere midway along the 3-4
bond. The diameter of the spheres is chosen so that the
volume of each of the spheres is eq ual to the volume of the
ethane cavity formed by an adjacent pair of methyl groups.
Of course, the rotational potential energy for isomeriza-
tion is unchanged. The advantage of this model is that
no superposition approximation is required to study the
intramolecular distribution of n-butane in a condensed
medium. We have found37 that by using this model we
can predict with reasonable accuracy the average intra-
molecular potential energy of the n-butane molecules
in the molecular dynamics calculation of Ryckaert and
Bellemans. 36 Furthermore, ifwe adopt this model for
the calculation of the quantity [see Eq. (2.41)]
A}J.n-butane - 2A}J. ethane = - RT lnqiwo cavity M ,
we obtain at 25 DC
(A}J.n-butane - 2A}J.etban.)tbeory = -1. 37 kcal/mole.
The experimentally observed value is
[A}J.n_butane - 2A}J. etbane]""pt. = - 1. 55 kcal/mole.
We therefore conclude that for n-butane we can accu-
rately calculate the change in the effective rotational po-
J. Chern. Phys., Vol. 67, No.8, 15 October 1977
3695
tential energy due to the solvent medium using only pair
cavity distribution by adopting this two cavity model.
For calculation of OA~HIl, however, we need to know
more than just how the rotational potential energy is
shifted by medium. Calculations of q~, and thus OA~HI),
superposition approximation is used. The problem is
clearly revealed by examining the experimental data for
1iA~~o~)ane (Fig. 5). By noting again that the error in the
superposition approximation when caVities overlap is
due to an effective overcounting we observe that the ap-
proximation
w3(lpropan.) =2w(L 54 A)
fits the data (see Fig. 5) reasonably well. This approx-
imation can be thought of as resulting from an explicit
elimination of an overcounted term which would be in-
cluded by the superposition approximation. Further-
more, this would be the exact result for an ordered
chain of three hard rods in one dimension. Thus, we
expect that for normal alkanes OA~HIl should contain a
term - kBT[BMw(l. 54 A)] which is independent of the con-
formation of the molecule. Here BM is the number of
bonds in a molecule of type M.
From the considerations above we have constructed
the following simple prescription for calculating OA~HI)
for normal alkanes: First, we use the rotational poten-
tial of Scott and Scheraga,38 the two cavity model of n-
butane, and the cavity distribution functions we have cal-
culated to obtain an intramolecular distribution function
for n-butane in liquid water. From this intramolecular
distribution function we can calculate the mole fraction
of n-butane molecules in the trans conformation X t and
in the gauche conformation Xr Next, we consider a ro-
tational isomeric model 39 of the conformational degree of
freedom of n-butane. The difference in potential energy
of the gauche states and the trans state,AE,is chosen so
that the rotational isomeric model predicts the previous-
ly calculated ratio Xg/X t The effective potential energy
of the molecule in the completely extended conformation is
taken to be - kB T[BMw(l. 54 All. Finally, for molecules
largerthann-butane we employ the same rotational isomer-
ic model, butt he effective interaction potential energy be-
tween cavities separated by more than three bonds is taken
to be a hard- sphere interaction potential with diameter of
3.7 A, plus the potential of mean force we have calcu-
lated for spherical apolar solutes in liquid water. Thus,
we apply the superposition approximation to yZ(1M) only
for pairs of cavities which never overlap. The following
equation summarizes the procedure just described:
nM
+ L' w(lri~) -riVI) + L
(o<y) o<>y=1
ul(1 r:~) - rl(~)1 )/kBT, (3.7)
where AE(O) is the rotational isomeric model energy dif-
ference between gauche and trans conformations of n-
butane in the ideal gas phase, nG(l M ) is the number of
gauche conformations of adjacent three bond segments
when the normal alkane molecule of type M is in config-
uration 1M (only discrete rotational isomeric configura-
tions are allowed), the summation ~;o<Y) is over pairs
3696 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect

TAB LE IV. Hydrophobic interaction free energy IiA~H!)
for normal alkanes dissolved in liquid water at 25"C and
1 atm pressure.
- IiA~HI) (in kcal/ mole)
structure of the nonrigid solute molecule. If the solvent
medium did not change the conformational structure
from its nature in the gas phase, then qZ =q:lgldM = 1;
see Eq. (2.45).

Nemethyand D. Transfer free energy for normal alkanes

M Experiment a This workb ScheragaC
ethane 2.16 2.41 1.2
propane 4.01 4.53 2.6
n-butane 5.87 6.59 4.2
n-pentane 7.53
8.32 6.0
n-hexane 9.43 9.89 7.6
n-heptane 11. 34 11.52 9.4
n-octane 13.08 13.20 11. 2
n-nonane 14.84
n-decane 16.52
aExperimental values are those compiled by Ben-Naim.10
See Eq. (3.1) for a definition of IiA~HI).
bCalculated from Eqs. (2.41) and (3.6) using the rota-
tional isomeric model described in the text.
C Predictions of Nemethy and Scheraga theory were read
from Fig. 6 in the second of Ref. 7.
of carbons Ci. and y which are separated on the alkane
chain by more than three bonds, and ul(r) is the Len-
nard-Jones perturbation for methane.
We have used this procedure to calculate OA~HIl at
25C for nonrigid normal alkanes up to n-decane. The
intramolecular distribution functions for n-butane in the
ideal gas and liquid water calculated by using the two
cavity model are shown in Fig. 60 For the isolated gas
phase molecule at 25C we find t:.E =785 cal/mole; for
n-butane in liquid water at 25C we find t:.E=267 cal/
mole. The possible conformational states of each mole-
cule were then enumerated explicitly. Any conformation
which required cavities separated by more than three
bonds to be closer than 3.7 A was excludedo The re-
sults obtained are presented in Table IVo In view of the
errors already present in the calculation of OA~~Il any
better agreement could only be fortuitous. Therefore,
in spite of the obvious refinements possible, such as a
continuous conformational model of the isolated mole-
cule, these calculations provide a correct qualitative
description of the experimentally observed solubilities
of nonrigid hydrocarbons in liquid water.
It is interesting to note that for normal alkanes larger
than propane the nonrigidity contributes significantly to
the free energies in Table IV. If the molecules were
completely rigid, we would find a lower partial molar
entropy of solution, and thus a higher chemical poten-
tial. For example, for n-butane
qt/q~lgldM=2.2 ,
where q~lgldM is the intramolecular partition function
[Eq. (2.42)] when the molecule is constrained to the
trans state. Therefore, the fact that n-butane is not
rigid stabilizes the molecule by an energy of about kBT.
Similarly, for n-decane we have found that accounting
for the nonrigidity lowers the chemical potential in liq-
uid water solution by about 4kB T. It is worth emphasiz-
ing that this stabilization is a manifestation of the effect
of the condensed phase in altering the intramolecular
The difference in the excess chemical potential of hy-
drocarbon solutes at infinite dilution in water and in a
hydrocarbon solvent is a measurable thermodynamic
quantity which can provide another test of the theory we
have presented. The transfer free energy is defined as
the difference in the chemical potential of a solute in
aqueous solution from its chemical potential in a hydro-
carbon solvent, L e., [t:.f1 M1H2 0 solvent - [t:.f1 MlhYdrocarbon'
The chemical potential [t:.f1M1H2o solvent' can be straight-
forwardly calculated from the procedures described in
Seco IlL Do However, to calculate [t:.f1M]hYdroCarbon we
must be able to characterize, at least approximately,
the structure of typical pure hydrocarbon solventso
Since the interaction potential energy between hydrocar-
bon molecules does not contain any quickly varying at-
tractive interactions, the structure of hydrocarbon sol-
vents is determined by excluded volume and packing
considerations. 2 D-22.31 To describe this packing we adopt
a very simple model. We assume the excluded volume
effect of the hydrocarbon solvent is similar to that of a
hard sphere solvenL The diameter of the hard spheres
a s is adjusted so that (1T/6)a~ is the same as the volume
of the hydrocarbon molecules as determined from van
der Waals' radii. The exact hard-sphere correlation
function can be calculated by the method of Verlet and
Weis021 22 Since many pairs of normal alkane solvents
mix as nearly ideal mixtures/o we consider only one
hydrocarbon solvent. Normal hexane is the alkane sol-
vent chosen since the Henry's Law constant for dissolv-
ing methane in n-hexane is accurately known. 41 Let
vC6H14 and PC6H14 denote the volume of a n-hexane mole-
cule and the molecular density of liquid C 6H14' respec-
tively. Then the diameter as and density P s for the
hard-sphere model of this solvent are chosen to satisfy
(3.8)
and
(3.9)
The value of VCSH14 can be calculated analytically by not-
ing that contributions to the volume due to the simulta-
neous overlap of three spheres is simply related to the
calculation of the low density correction to the super-
position approximation for the potential of mean force
between three hard spheres. 42 We find as = 5. 8 A. The
hard-sphere model for the hydrocarbon solvent correla-
tion function is inserted into the integral equations,
(2.29) to calculate the pair distributions for methane
cavities in the hydrocarbon solvento The intramolecu-
lar distribution function calculated for n-butane at 25C
in this hydrocarbon solvent is also shown in Fig. 60 The
difference in the energies of the gauche and trans states
for the appropriate rotational isomeric model is found to
be 608 cal/mole. The mole fraction of n-butane mole-
cules in the trans state is found to be

J. Chern. Phys., Vol. 67, No.8, 15 October 1977

 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
[XtlbYdrocarbon = 0.59.
It is interesting to compare this value to the values of
X t found for n-butane molecules in the ideal gas phase
and in liquid water at 25C (see Sec, III. C). We have
found that
[Xtlideal gas = 0.65,
and
[Xtlwater=0.44.
[It should be emphasized again that even after adoption
of our simple model for the hydrocarbon solvent the cal-
culation of the cavity distribution function for methane
cavities in a hard sphere solvent is approximate. The
errors in our calculation of these cavity distribution
functions are of the size typical of Percus-Yevick-like
approximations for a high density hard sphere fluid (see
Sec. II. C.). A more nearly exact calculation of the
cavity distribution function of methane cavities infinitely
dilute in a hard-sphere solvent has been made. 37 It is
then found that for n-butane dissolved in our model of a
hydrocarbon solvent [XtlhYdroCarbon =0.52. For the pur-
poses of this work we apply the same theoretical ap-
proach to both liquid water solvent and the hydrocarbon
solvent so that a reasonable basis of comparison may be
established.l
The calculation of ilJ.1.M for hydrocarbon solvent fol-
lows exactly the procedure discussed in Sec. III. D. In
order to avoid introduCing adjustable parameters to de-
scribe the methane-solvent mean field perturbation po-
tential we have used the experimentally determined33 ,4l
excess chemical potential at infinite dilution for methane
in each solvent. Thus, only the calculation of qZ is re-
quired in Eq. (2.41).
The results that we obtain for the transfer free ener-
gy of n-alkanes between water and the hydrocarbon sol-
vent are compared with the experimental results of
McAuliffe 43 in Fig. 7. The least squares straight line
fit to our calculated values yields a slope of 853 call
mole. The slope obtained from the experimental values
is 884 cal/mole. Note that in McAuliffe's work the hy-
drocarbon solvent in each experiment is the neat liquid
hydrocarbon being studied. Therefore, our calculations
would correspond precisely to McAuliffe's experiments
only if the different hydrocarbon solvents mixed ideally.
Several of the normal alkanes do form approximately
ideal mixtures,40 and it has been argued that errors from
this source should be small,l2 We believe therefore that
these calculations provide a qualitatively correct de-
scription of these transfer studies.
The transfer free energies shown in Fig. 7 have often
been correlated with the surface area of the solute mole-
cules. 9,44,45 Insofar as the surface area is proportional
to the number of cavity particles in the solute molecule,45
the calculations shown in Fig. 7 confirm this correla-
tion. Using estimates of Harris et al. 4l and Reynolds
et al. 4o for the surface area increment upon increasing
the chain length of a normal alkane by one carbon and the
theoretical results shown in Fig. 7, we obtain a value
of 22 cal/moleAz for the slope of the transfer free en-
ergy with respect to surface area of the solute molecule.
J. Chern. Phys., Vol. 67, No.8, 15 October 1977
3697
Of course, surface area considerations do not playa
direct fundamental role in our theory, However, the
effects of nonrigidity are fundamental. It is interesting
to note that in our calculations the lowering of ilJ.1.M due
to conformational degrees of freedom is approximately
cancelled by taking the difference to obtain a transfer
free energy. For example, the difference between
In(qZ/q~lgldM) in the two solvents is less than 20% the
value of In(qtlq~lgldM) in the water phase. Thus, the
nonrigidity of the solute molecules contributes a rela-
tively smaller amount to the slope of the transfer free
energies with respect to the number of carbons than it
does to OA~HI).
IV. DISCUSSION OF RESULTS
In Sec. III we tested our microscopic theory by com-
paring its predictions for measurable thermodynamic
quantities with experimentally observed values. In each
case the theory yielded qualitatively correct descrip-
tions of thermodynamic quantities which have been
thought to be important to an understanding of hydro-
phobic phenomena. In this section we discuss predic-
tions of the theory which are less amenable to experi-
mental verification.
A. Radial distribution functions
The results of calculations of the radial distribution
functions gAA(r) and gAW(r) for several diameters and
temperatures appear in Figs. 8-13. We now discuss
several conclusions which may be drawn from these re-
sults.
We first compare the potential of mean force between
two solutes in water with the same quantity for a hard
sphere solvent which has as =2.7 A and the same density
as liquid water. Figure 8 shows typical results. It can
be seen that in both solvents, the potential of mean force
oscillates with a wavelength of about 3.0 A, determined
by the diameter of the solvent. We note that the poten-
tials of mean force are similar near the contact region.
Thus, no peculiar attractive interaction can be identified
by studying gAA (r) near contact only. For 1. 2a AA S r
10
Q)
(5
E
....... 8
0 u
.....,.
~
-;: 6
J!
jg
0
t= 4
~:::!:
<!
c;o
2
4 5 6 7 8 9 10
FIG. 7. The free energy of transfer 6A.lir-.r)=[ilPM1H~8olvent
- [ilPMlbydrocarbon for normal alkanes from an apolar hydrocarbon
solvent (see text) to liqUid water at 25C and 1 atm pressure.
The circles are the experimental data of McAuliffe (Ref. 38).
The triangles are the theoretical results.
 3698 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect

T =30C 3.50
- - hard sphere solvent (0".=2.7)\) O"A=3.0il
0.8 - - water solvent O"A =40il
O"A =5.oll O"A =5.0il
2.80
0.4 T =35C

0.0 ~2.10
~

3 -0.4 J lAO

0.70

5.0 6.0 70 8.0 9.0 10.0 11.0 OL--rO~.o~~~--~~--~--~~--~~~

rOt)
FIG. 8. The potential of mean force (in units of kBT) between
hard spheres of diameter (JA = 5.0 A infinitely dilute in liquid
water at 30 'C (the solid line), and in a hard-sphere solvent
with diameter 2.7 A and the same density as liquid water at
30C and 1 atm pressure (dashed line). Note that for r> (JA,
lngAA(r) =w(r).
S 20'AA, however, the potential of mean force in the
water solvent is Significantly lower than the potential of
mean force in the hard-sphere solvent.
We next compare the radial distribution functions ob-
tained for different size solutes in liquid water. Figures
9 and 10 show that the effective interaction between
solute molecules becomes more attractive as the size of
the solute molecule increases, Furthermore, the inter-
action between the solutes becomes more sensitive to
changes in temperature as the size of the solute in-
creases, The effect of a change in temperature is also
shown in Figs. 11 and 12. From comparison of the re-
sults shown in Figs. 8 and 12 one concludes that as the
temperature is raised the potential of mean force in
water becomes less unusual, and more like the potential
of mean force in a hard-sphere solvent.
2.2 4.4 6.6 8.8 11.0
(r-O"A ) (a)
FIG. 10. The radial distribution functions gAA(r) for hard
spheres of various diameters infinitely dilute in liquid water
at 35C and 1 atm pressure.
We next consider the A W radial distribution functions.
Figure 3 shows typical results for gAW(r). The contact
value of gAW(r) increases monatomically with increasing
a A until a A becomes about 4.5 A, at which point GAW(rW
+ a A/2) levels ofL This behavior can be seen from Fig.
3 or Table 1. [Note that since gAW(r) - cAW(r) is contin-
uous, see Eqs. (2,27), G AW (r W+O'A/2) is given by -co
in Table I.] These results should be compared to the
results predicted by the semiempirical scaled particle
theories of Pierotti8 and Stillinger. 13 Figure 13 shows
the gAW(r) we calculate for methane in water at 25C.
Also indicated are the contact values of GAW(rw + a A/2)
calculated from the scaled particle theories. The scaled
particle theories predict contact values GAW in Eqs,
(2.22) and (2.23) which are smaller than the ones we
calculate, and they predict that GAW is a maximum for
sphere diameters near a A =1, 3 A. When the size of the
solute becomes very much larger than the size of the
solvent molecules, the solute molecule appears to the

1.2 r----,------,-----r----,----.,.----~....,

3.50 - T=4C
O"A=3.0il 0.8 - - T=50C
O"A =4.0il O"A = 3.oil
O"A=5.0)\
2.80 T=4C 0.4

2.10 ...... -
-.::-
---.r

0> 140

0.70
-1.2

3.0 4.0 5.0 6.0 70 8.0 9.0

0L--'0~.0n--n2~.2'--~4~.4--6~.~6-~8~.8~-~1+1~.0-~
(r-O"A) (a)
FIG. 9. The radial distribution functions gAA (r) for hard
spheres of various diameters infinitely dilute in liquid water
at 4 'C and 1 atm pressure.
r (.a)
FIG. 11. The potential of mean force (in units of kBT) between
hard spheres of diameter (JA = 3.0 A infinitely dilute in liquid
water at 1 atm at temperatures of 4 (solid line) and 50 'C
(broken line). Note that for r>(JA' IngAA(r) =w(r).

J. Chem. Phys., Vol. 67, No.8, 15 October 1977

 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect 3699

1.4..----r----r--,----,---,---,---,--, gAA(r) near contact as well as by GAW(rw+ O'A/2). On the

- T=4C basis of these three theoretical values for OA~~I) it seems
1.0 - - T=30C likely that the theory we have presented and the semiem-
........ T=50C pirical scaled particle theories bracket the correct con-
erA=50A tact value GAW(rW+ O'A/2) with our result being somewhat
0.6
too high.
0.2
B. Three molecule correlations
~

'3 -0.2
I
Many of the physical ideas about hydrophobic phe-
nomena should be examined by studying correlations be-
-0.6 tween more than two molecules. For example, it is of
interest to know how the correlations between two water
molecules change due to the presence of an apolar solute
nearby. These correlations involve real molecules and
not cavities which can overlap. Since they do not over-
-1.4 5.0 6.0 7.0 80 90 10.0 110 120
r (.II)
lap, their correlations can probably be described qual-
itatively by the superposition approximation. By employ
FIG. 12. The potential of mean force (in units of kBT) between
ing this approximation we present below a picture of the
hard spheres of diameter O"A = 5.0 A infinitely dilute in liquid
preferred locations of molecular centers implied by our
water at 1 atm pressure and temperatures of 4 (solid line). 30
(dashed line). and 50C (dotted line), Note that for r> O"A. theory. Of course, we can say nothing about preferred
lngAA (r) = w(r). orientational arrangements of water molecules near
apolar solutes.

solvent to be a hard walL In this limit an exact theory Consider the three body conditional probability
must satisfy46 p~t.J'M,,(RIR', R"), which is defined as the conditional
probability of finding a molecule of type M with center at
lim PWGAW(rW + O'A/ 2 ) =p/kBT, R, given that a molecule of type M' has its center at R',
a A" eo
and a molecule of type Mil has its center at R" . By us-
where p is the pressure. The semiempirical scaled ing a superposition approximation for the distribution of
particle theories are constructed to satisfy Eq. (4.1)0 molecular centers we obtain
With the theory we have presented it is not clear whether
or not Eq. (4.1) is satisfied. It is known that if the sol- p~lJ, M,,(R 1R' , R") '" PM gMM' (I R - R' I) gil M"( IR - R" I)
vent-solvent correlation function satisfies certain (4.3)
strong conditions,47,48 which are not satisfied for liquid [It should be noted that since the functions on the right-
water, then the type of approximation we use in Eq. hand side of Eq. (4.3) are orientationally averaged, Eq.
(2.29) implies 47 ,48 (4. 3) is somewhat different than the usual superposition
approximation.] Within this approximation we can illus-
lim PwG AW(O'A/2 + rw) =Pw(k BT)-l (ap/apw)l/Z (4.2) trate the preferred locations of water molecules around
rIA""
an apolar solute. Figures 14 and 15 show two views of
For all the solutes we have considered 0'A is small the surface gAw(1 R - R'I )gww(1 R -Rill) for O'A = 3. 7 A,
enough that we are not near the walllimiL However, it
is interesting to note the large disparity between Eqs.
6.0 24
(4.1) and (4.2). For liquid water at biological tempera-
tures and 1 atm pressure [a(p/k BT)/apwj1/z is about 400, I
andp/(kBTPw) is about 10- 5 5.0 / 20
/
Because of the ambiguities regarding ull~(r), compari- 4.0 / 16
son of the results for All A is not an entirely satisfying ... I
/
way to discriminate between the semiempirical scaled I
~
<[ 3.0 12 ~
particle theories and the theory we have presented. A 01 /
I c:
more revealing comparison is obtained by forming a (2)
hybrid theory to study oA~~Il. In particular, we com-
2.0
(1) I 8
bine the g AA (r) that we have calculated with the GAW(rW
+ 0' A/2) from the semiempirical scaled particle theories 1.0 4
to form the interpolation equation (2.38). From this
hybrid procedure we estimate that with Pierotti's ap- 020 3.0 40 50 6.0 7.0 8.0 0
proximation 8 we would predict oA~~Il to be - 1. 9 kcal/
r UO
mole at 25C; with the Stillinger13 theory for GAW(rw
+ O'A/2) we would predict M~~l) to be- 2.1 kcal/mole at FIG. 13. The A-W radial distribution function gAW(r) for O"A
25C. Recall that our result for OA~~I) was - 2. 4 kcal/ =3.7 A at 25C. The dashed line refers to n(r), the number of
neighbors in a shell of radius r. The arrows indicate the pre-
mole. Of course, the scaled particle theories cannot dictions of the semiempirical scaled particle theories of (1)
calculate OA~~I) without our results for gAA(r). The val- Pierroti (Ref. 8) and (2) Stillinger (Ref. 13) for the contact
ues of OA~~I) are strongly affected by the behavior of value GAW(rW+O"A/2).

J. Chern. Phys., Vol. 67, No.8, 15 October 1977

3700 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect

-~
8.0 8.o[
Dr gAw(RAW)gww(Rwwi

4.0 40t

2.0

~.
oco .050 LO.o 1.5.0 2.0.0
.
250 3.0.0
10.0 12.0

8 (radians)
FIG. 14. The conditional density of water molecules surround- FIG. 15. Another view of Fig. 14.
ing a fixedAW pair in contact (see text). (JA ~3. 7 A at T=25'C.

R' =0, I R' - R" I =3.2 A at 25 c. The sharp disconti- small Rand e in Fig. 17 because solute molecules and
nuities would be smoothed offby accounting for the softness water molecules cannot overlap. This complicated but
of the repulsive reference potential (see Fig. 2). As nonsignificant structure has been removed from Fig. 17
might have been expected the preferred position for the and a flat surface substituted in the overlap region in
second water is in contact with both the first water and order to draw attention to the significant information to
with the A particle. As the separation of the two water be gained. Figure 17 shows that the presence of the sol-
molecules is increased while holding the A- W separa- ute causes a buildup in the water density in the region
tions fixed (increasing e with R fixed larger than 3.2 A in adjacent to the solute. It is not clear whether or not the
Fig. 14) gww(r) is traced out. The secondary maximum results shown in Fig. 17 describe what is frequently re-
in gww(r), near e = rr/2 in Fig. 14, is due to an energeti- ferred to as a structure making effect. The correspond-
cally favorable configuration in which two water mole - ing surface for a solution of an apolar solute in a hard-
cules are simultaneously hydrogen bonded to a third in- sphere solvent is qualitatively similar.
termediate water molecule. According to these calcula-
tions the presence of an A particle does not disrupt this C. Osmotic seeond vi rial coefficients
feature of the liquid water structure.
A sensitive measure of gAA(r) is the osmotic second
If the two fixed particles are both A particles, then vi rial coefficient defined by
p~lA (RI R / , R") would provide conditional density of wa-
ter molecules given that the A particles are fixed at R' (4.5)
and R". Figure 16 shows the surface gAW( IR - R' I)
xgAW( I R - R" I ) for the configuration I R' - Rill = 3.7 One way to obtain Ba experimentally is to observe devia-
= uA at 25 c. The origin of the coordinate system is tions from Henry's Law. However, since the solubility
taken as midway between the two fixed A particles. of simple apolar species in water is quite low, Henry's
Again it is seen that the preferred positions of water Law is obeyed to an excellent approximation. There-
molecules are in contact with both the A particles.
With these pair correlation functions we can also il-
8.0
lustrate the alteration of the water structure due to the
presence of the A particle. We note that if the A par-
ticle were removed far away from the two water mole-
cules, then p~lw(RI R / , R") -Pwgww( I R - Rill). However,
when the A particle is relatively near the two water
molecules p~w(R IR / , R") will differ from Pwgww( IR
- Rill). This difference p~~w(R I R / , R") - Pwgww( IR
- R" I ) reflects the change in the water structure due to
the presence of the A particle. If we adopt the super-
position approximation, then

p~ [p~~w(R IR / , R") - I
Pwgww( R - Rill)]

4.0 12.0
=hAW(IR/-R"I)gww(IR-R"I) (4.4) 2.0

This surface is plotted in Fig. 17 for UA = 3.7 A, R =0, FIG. 16. The conditional density of water molecules surround-
I R - R/I = 3. 2 A at 25C It should be noted that the sol- ing a fixed AA pair in contact (see text). (JA = 3.7 A and T
ute molecule excludes water molecules from a region at =25C.

J. Chern. Phys., Vol. 67, No.8, 15 October 1977

 L. R. Pr att and D. Chandler: Theory of the hydrophobic effect 3701

measure of the interactions between segments separated

by a large distance along the polymer chain. 39 From
the point of view of these theories our results would cor-
respond to characterizing water as a "bad" solvent, the
effect of which would be to contract the average dimen-
sion of the polymer.
The trends discussed in the previous section are also
evident in the results for the osmotic second vi rial coef-
ficient in water. At the lower temperature studied the
effective attractive interaction increases with the size
of the solute. As the temperature is raised the attrac-
~ 6---2'O--;m---W---80-- 100 --!2b tive interaction decreases in strength, and the results
Rww (J\) become more hard sphere-like.
FIG. 17. The alteration of the water density surrounding a D. Conformations of flexible molecules
central water molecule due to the presence of an A molecule
in contact with the central water (see text). 0"A = 3. 7 A and T We have studied the effect of the liquid water medium
=25C. The dark lines indicate the zero contour. on the mean square end-to-end length, (L ~, for normal
alkanes. This is defined by
fore, the measurement of B2 for simple inert gases has (4.7)
proven very difficult.
This quantity can be evaluated straightforwardly by the
We have calculated osmotic second virial coefficients procedure outlined in Sec. m. D. To compare the rela-
of hard spheres in water for several diameters and tem- tive effect of liquid water with the effect which might be
peratures. The direct use of Eq. (4.5) for these numer- expected from typical hydrocarbon solvents we have also
ical calculations is unsatisfactory, because the value of calculated (L2) for a hard-sphere solvent which is char-
B2 obtained is very sensitive to slight errors in gAA(r) acterized by Eqs. (3.8) and (3.9). The results of Sec.
at large r. We observe that Eq. (2.30) provides an al- III. E. indicate that this hard-sphere solvent provides
ternative formula a reasonably accurate approximation to a hydrocarbon
solvent for the calculation of intramolecular properties
(4.6)
of nonrigid solutes.
This formula is preferable for numerical calculations, The values of (L2) calculated for n-alkanes in the two
because further numerical integration is required only solvents are compared with (L2) Ideal in Fig. 18. Here,
to calculate CAA(O), and cAA(r) has a finite range. Fur- (L 2 >ldeal is the average obtained when using the gas
thermore, Eq. (4.6) allows us to use precise thermo- phase intramolecular distribution s~Ol(1M)' Both sol-
dynamic data 49 for the compressibility of pure water vents cause the solutes to fold into more compact aver-
in the calculation of B 2 Since the two terms on the age conformations in solution than in the gas phase.
right-hand side of Eq. (4.6) are of opposite sign and However, the results in Fig. 18 indicate that some non-
large compared to the size of B 2 , errors in the value of
hww(O) are magnified. Even after using thermodynamic
data to calculate hww(O) we find that the value of B2 is TABLE V. Osmotic secon:! virial coefficient B2 (A 3) for hard
very sensitive to the pure water structure factor at non- spheres in water and a hard-sphere solvent.
zero wave vector. We have found that a systematic er-
ror of magnitude 5 x 10-4 in the experimental water
structure factor can change the value of B2 by as much ~AA 3.0 A 3.5 A 4.0 A 4.5 A 5.0 A
as a tenth of (21Tdl"'/3). Thus, extremely small errors in Liquid water solvent a
the experimental water structure factor represent the
20 11.9 8.2 -5.5 -34.4 -79.8
largest possible source of error in the values of B2 we
35 15.3 18.6 14.6 -6.5 - 53. 0
report here. 50 18.8 28.4 33.0 19.8 -22.7
The values obtained for B2 in the water solution are Hard-sphere solvent b
compared to the values in the corresponding hard sphere
20 16.0 27.8 41. 0 52.7 58.5
solvent in Table V. The hard-sphere solvent has as 35 16.3 28.3 41. 9 54.4 61. 5
= 2. 7 A and the same density as water at the specified 50 16.6 28.9 43.2 56.8 65.7
temperature and 1 atm pressure. These results indicate
a dramatic difference between water and the hard-sphere acalculated from Eq. (4.6).
solvent. This difference arises from differences in bCalculated from the integral equation described in the text
the radial distribution function outside the first minimum. with a hard-sphere fluid solvent instead of water. The hard-
sphere fluid pair correlation function was obtained from the
Thus, the value of B2 appears to be a sensitive indicator
Verlet-Weis method (Refs. 21 and 22). The diameters for the
of a hydrophobic interaction which is significantly more hard spheres was taken to be 0" s = 2rw = 2.7 A, and the density
attractive than the interaction in a corresponding non- of the hard sphere fluid solvent Ps was taken to be the same as
associated solvent. In statistical theories of polymer that for liquid water at 1 atm pressure and the specified tem-
configurations the value of B2 is frequently used as a perature.

J. Chern. Phys., Vol. 67, No.8, 15 October 1977

3702 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
o Liquid water
5.0 6. n - hexane
'"ad:
T = 25C
"
.S>
4.0
,,
0
=>
3D
,
.......'"
"'...J ~ sions which can be drawn from the work we have pre-
'-./
2 ..0
c;
Q)
:<::>
10
/'-.
'"...J
'-./
4 5 6 7 8 9
nc
FIG. 18. The difference between the mean square length of n-
alkanes in the ideal gas phase and in solution. The number of
carbons in the alkane chain is denoted by nco The circles
represent the results in liquid water solution; the triangles
represent the results for the hard-sphere solvent model of n-
hexane (see text). The temperature is 25C.
rigid alkanes will be shorter in the hydrocarbon solvent.
This behavior results from the detailed differences in
the water cavity distribution functions significantly away
from contact. When the second to last term inEq. (3.7)
is excluded from lnyZ(l M ) the quantity shown in Fig. 18
is a monatomically increasing function of nc ' for nc ~ 5.
Furthermore, it can be seen from Fig. 18 that the aver-
age length of the molecules which give local maxima
correlates closely with distance, which locates the first
minimum in gAA (r). In the water solvent the cavity dis-
tribution function essentially reaches its asymptotic
value of 1 for separations larger than 6.0 A. But the
cavity distribution for the hard-sphere model of the hy-
drocarbon solvent, with as = 5. 8 A,has nontrivial struc-
ture for separations between 6 to 12 A. From 5.5 to
7. 5 A the cavity distribution function in the hydrocarbon
solvent is less than 1 and also has negative slope. The
cavity distribution in the water solvent is relatively
slowly varying in this region. Thus, n-hexane, n-hep-
tane, and n-octane, which are expected to have average
lengths in the range 5.5 to 7.5 A, are slightly shorter
in the hydrocarbon solution. For separations between
7. 5 to 12 A the cavity distribution function in the hydro-
carbon solvent has a positive slope, and thus n-nonane
and n-decane are again shorter in the water solution.
From these considerations it seems likely that for
molecules larger than n-hexane the values we calculate
for (L2) may change slightly if the hydrocarbon solvent
is changed to another nonassociated solvent with a much
different average size than n-hexane. Thus, whenever
the length parameters which determine the significant
features of the solvent structure are of the same order
of magnitude as the possible conformational distance
changes involved, a detailed microscopic analysis seems
to be necessary. In view of this sensitivity to details
of the solvent structure, it seems that a more sophisti-
cated characterization of the hydrocarbon solvent struc-
ture than our simple hard sphere model could result in
changes in detail of Fig. lB. However, these results
are qualitatively indicative of the care that should be
J. Chem. Phys., Vol. 67, No.8, 15 October 1977
taken to include the effects of the medium in the study
of conformational properties of nonrigid molecules in
condensed phases.
V. CONCLUSIONS
In this section we discuss several significant conclu-
\
\ sented.
\
h
First of all the Ornstein-Zernike-like equation (2. 27)
and the closure relations (2.29) seem to provide a
qualitatively correct description of the radial correla-
ill tions between solute molecules and between solutes and
water for dilute aqueous solutions of apolar solutes.
Although this theory was obtained with heuristic argu-
ments, it seems to contain some essential features of
any correct theory of hydrophobic phenomena. Per-
haps the most questionable part of our theory is the
Ornstein-Zernike-like equation which ignores the ex-
plicit role of angular correlations between water mole-
cules and apolar solutes. These angular correlations
are treated only implicitly by the semiempirical use of
the exact pure water correlation function. The theory
predicts measurable thermodynamic quantities which are
always in qualitatively correct agreement with experi-
ment. This fact would indicate that our theory is re-
liable and that it therefore can be used to clarify some
aspects of hydrophobic phenomena which are speculative.
We have found that the hydrophobic interaction is not
manifested by anomalous behavior of the potential of
mean force near contact. This conclusion seems to be
contrary to what has been previously believed. Io But
many thermodynamic quantities are sensitive to changes
in the potential throughout its range, and these thermo-
dynamic quantities can be dramatically different in water
solvent compared to nonassociated solvents.
Ben-Nairn's OA~HI), defined by Eq. (3.1), provides a
convenient test of microscopic theories of hydrophobic
interactions. The new result Eq. (2.44) explicitly shows
that for nonrigid as well as rigid molecules the calcula-
tion of OA1H1 ) focuses directly on structural properties
of the hydrophobic interaction and is reasonably free of
adjustable parameters. The structural quantity probed
by measurement of OA~HI) is the value of a cavity dis-
tribution function when the cavities are situated in the
bonding configuration appropriate to the molecule M.
The cavity distribution functions frequently change very
rapidly with displacement of the cavities. Therefore,
it is usually a bad approximation to assume that OA~HI)
directly describes the energetiCS of clusters of real
apolar molecules in some other configuration.
While OA~HI) does decrease with increasing tempera-
ture, the decrease occurs for a trivial reason. There
appears to be no microscopic interpretation which is
compatible with the claim lO that the hydrophobic inter-
action increases in strength as the temperature is in-
creased. We find that as the temperature is raised the
potential of mean force between two hard spheres in
liquid water tends to become more like the potential of
mean force between two hard spheres in a corresponding
nonassociated solvent.
 L. R. Pratt and D. Chandler: Theory of the hydrophobic effect
When applied to multipoint cavity distribution func-
tions the superposition approximation is qualitatively
wrong for configurations in which cavities overlap. An
important reason for this behavior is the failure of the
superposition approximation to satisfy an exact limiting
condition for hard spheres [Eq. (3.4)]. Since multi-
point cavity distribution functions play an important role
in the theory of chemical equilibria and intramolecular
structure in condensed phases, the problem of devising
simple improvements over the superposition approxi-
mation deserves renewed attention.
The linearity of the results of transfer studies is due
to the fact that the dominant contribution to the chemical
potential of a multigroup molecule is nearly extensive in
the number of groups. Surface area arguments are not
necessary to provide a correct microscopic description
of transfer studies on small molecules.
Liquid water tends to reduce the average spatial ex-
tension of n-butane from the result which would be found
in a dense nonassociated liquid solvent. However, for
larger molecules a detailed microscopic analysis is
required to determine whether the molecule will be
more or less extended in the water solvent than in the
nonassociated solvent. Thus, it is not necessarily true
that nonrigid molecules always fold to more compact
conformations in liquid water than in nonassociated sol-
vents. This analysis as well as earlier work23 stresses
the importance of liquid environments on molecular con-
formations. These effects must not be ignored if one
wishes to understand the properties of nonrigid solute
species in condensed phases, and the behavior of neigh-
boring solvent molecules.
ACKNOWLEDGMENTS
While working on the calculations reported in this
article we have benefitted from discussions with Hans
C. Andersen, H. L. Friedman, H. G. Hertz, Frank H.
Stillinger, Jr., and Eduardo Waisman. Much of our
discussion in Sec. IV was motivated by a conversation
with Professor Hertz. Doctor Stillinger described to
us unpublished computer simulation results which clari-
fied our thoughts concerning the integral equation we
use to calculate pair correlation functions. Conversa-
tions with Dr. Waisman helped illuminate the signifi-
cance of the structure of our integral equation in the
wall limit. Some of our ideas concerning corrections
to the superposition approximation originated during
a conversation with Professor Andersen. Professor
Friedman and Dr. Stillinger made helpful comments on
the first draft of this article.
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J, Chem. Phys., Vol. 67, No.8, 15 October 1977